US20230100271A1 - Genetic polymorphisms associated with cardiovascular diseases, methods of detection and uses thereof - Google Patents

Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with cardiovascular diseases, particularly coronary heart disease (especially myocardial infarction) or hypertension. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
• This application is a divisional application of U.S. non-provisional application Ser. No. 16/739,408, filed on Jan. 10, 2020, which is a divisional application of U.S. non-provisional application Ser. No. 15/409,162, filed on Jan. 18, 2017, which is a continuation application of U.S. non-provisional application Ser. No. 13/964,571, filed on Aug. 12, 2013, which is a continuation application of U.S. non-provisional application Ser. No. 13/486,424, filed on Jun. 1, 2012, which is a divisional application of U.S. non-provisional application Ser. No. 12/500,378, filed on Jul. 9, 2009 (issued as U.S. Pat. No. 8,216,786 on Jul. 10, 2012), which claims priority to U.S. provisional application Ser. No. 61/134,522, filed on Jul. 9, 2008, the contents of each of which are hereby incorporated by reference in their entirety into this application.
FIELD OF THE INVENTION
• The present invention is in the field of cardiovascular diseases (CVD), particularly coronary heart disease (CHD), including myocardial infarction (MI), and hypertension. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with CVD. The SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for such uses as identifying an individual who has an increased or decreased risk of developing CVD (particularly CHD, such as MI, and hypertension), for early detection of the disease, for providing clinically important information for the prevention and/or treatment of CVD, for predicting progression or recurrence of CVD, for predicting the seriousness or consequences of CVD in an individual, for determining the prognosis of an individual's recovery from CVD, for screening and selecting therapeutic agents, and for predicting a patient's response to therapeutic agents such as evaluating the likelihood of an individual responding positively to a therapeutic agent such as a statin, particularly for the treatment or prevention of CVD (such as CHD, particularly MI, and hypertension). The SNPs disclosed herein are also useful for human identification applications. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.
BACKGROUND OF THE INVENTION
• Cadiovascular Diseases (CVD)
• Cardiovascular diseases (CVD) include, for example, coronary heart disease (CHD) and hypertension. CHD includes, for example, myocardial infarction (MI).
• Coronary Heart Disease (CHD), including Myocardial Infarction (MI)
• The present invention relates to SNPs that are associated with the occurrence of coronary heart disease (CHD), particularly myocardial infarction (MI).
• CHD is defined in the Framingham Heart Study as encompassing MI, angina pectoris, coronary insufficiency (which is manifested as ischemia, that is, impaired oxygen flow to the heart muscle), and coronary heart disease death (Wilson et al., Circulation 97:1837-1847 (1998)). CHD may be recorded through clinical records that indicate the following interventions: coronary artery bypass graft (CABG), angioplasty (e.g., percutaneous transluminal coronary angioplasty (PTCA)), and revascularization (stent placement), in addition to clinical records of MI, angina, or coronary death.
• As used herein, CHD is defined in accordance with how this term is defined in the Framingham Heart Study (i.e., as encompassing MI, angina pectoris, coronary insufficiency, and coronary heart disease death). Angina pectoris includes unstable angina in particular.
• The SNPs described herein may further be useful for such cardiovascular events as vulnerable plaque and stroke.
• Myocardial Infarction (MI)
• Myocardial infarction (MI), also referred to as a “heart attack”, is the most common cause of mortality in developed countries. The incidence of MI is still high despite currently available preventive measures and therapeutic intervention. More than 1,500,000 people in the U.S. suffer acute MI each year, many without seeking help due to unrecognized MI, and one third of these people die. The lifetime risk of coronary artery disease events at age 40 is 42.4% for men, nearly one in two, and 24.9% for women, or one in four. D. M. Lloyd-Jones, Lancet 353:89-92 (1999).
• MI is a multifactorial disease that involves atherogenesis, thrombus formation and propagation. Thrombosis can result in complete or partial occlusion of coronary arteries. The luminal narrowing or blockage of coronary arteries reduces oxygen and nutrient supply to the cardiac muscle (cardiac ischemia), leading to myocardial necrosis and/or stunning. MI, unstable angina, and sudden ischemic death are clinical manifestations of cardiac muscle damage. All three endpoints are part of acute coronary syndrome since the underlying mechanisms of acute complications of atherosclerosis are considered to be the same.
• Atherogenesis, the first step of pathogenesis of MI, is a complex interaction between blood elements, mechanical forces, disturbed blood flow, and vessel wall abnormality that results in plaque accumulation. An unstable (vulnerable) plaque was recognized as an underlying cause of arterial thrombotic events and MI. A vulnerable plaque is a plaque, often not stenotic, that has a high likelihood of becoming disrupted or eroded, thus forming a thrombogenic focus. MI due to a vulnerable plaque is a complex phenomenon that includes: plaque vulnerability, blood vulnerability (hypercoagulation, hypothrombolysis), and heart vulnerability (sensitivity of the heart to ischemia or propensity for arrhythmia). Recurrent myocardial infarction (RMI) can generally be viewed as a severe form of MI progression caused by multiple vulnerable plaques that are able to undergo pre-rupture or a pre-erosive state, coupled with extreme blood coagulability.
• The current diagnosis of MI is based on the levels of troponin I or T that indicate the cardiac muscle progressive necrosis, impaired electrocardiogram (ECG), and detection of abnormal ventricular wall motion or angiographic data (the presence of acute thrombi). However, due to the asymptomatic nature of 25% of acute MIs (absence of atypical chest pain, low ECG sensitivity), a significant portion of MIs are not diagnosed and therefore not treated appropriately (e.g., prevention of recurrent MIs).
• MI risk assessment and prognosis is currently done using classic risk factors or the recently introduced Framingham Risk Index. Both of these assessments put a significant weight on LDL levels to justify preventive treatment. However, it is well established that half of all MIs occur in individuals without overt hyperlipidemia.
• Other emerging risk factors of MI are inflammatory biomarkers such as C-reactive protein (CRP), ICAM-1, SAA, TNF α, homocysteine, impaired fasting glucose, new lipid markers (ox LDL, Lp-a, MAD-LDL, etc.) and pro-thrombotic factors (fibrinogen, PAI-1). These markers have significant limitations such as low specificity and low positive predictive value, and the need for multiple reference intervals to be used for different groups of people (e.g., males-females, smokers-non smokers, hormone replacement therapy users, different age groups). These limitations diminish the utility of such markers as independent prognostic markers for MI screening.
• Genetics plays an important role in MI risk. Families with a positive family history of MI account for 14% of the general population, 72% of premature MIs, and 48% of all MIs. R.R. Williams, Am J Cardiology 87:129 (2001). In addition, replicated linkage studies have revealed evidence of multiple regions of the genome that are associated with MI and relevant to MI genetic traits, including regions on chromosomes 14, 2, 3 and 7, implying that genetic risk factors influence the onset, manifestation, and progression of MI. U. Broeckel, Nature Genetics 30:210 (2002); S. Harrap, Arterioscler Thromb Vasc Biol 22:874-878 (2002); A. Shearman, Human Molecular Genetics 9:1315-1320 (2000). Recent association studies have identified allelic variants that are associated with acute complications of CHD, including allelic variants of the ApoE, ApoA5, Lpa, APOCIII, and Klotho genes.
• Genetic markers such as single nucleotide polymorphisms (SNPs) are preferable to other types of biomarkers. Genetic markers that are prognostic for MI can be genotyped early in life and could predict individual response to various risk factors. The combination of serum protein levels and genetic predisposition revealed by genetic analysis of susceptibility genes can provide an integrated assessment of the interaction between genotypes and environmental factors, resulting in synergistically increased prognostic value of diagnostic tests.
• Thus, there is an urgent need for novel genetic markers that are predictive of predisposition to CHD such as MI, particularly for individuals who are unrecognized as having a predisposition to MI. Such genetic markers may enable prognosis of MI in much larger populations compared with the populations that can currently be evaluated by using existing risk factors and biomarkers. The availability of a genetic test may allow, for example, appropriate preventive treatments for acute coronary events to be provided for susceptible individuals (such preventive treatments may include, for example, statin treatments and statin dose escalation, as well as changes to modifiable risk factors), lowering of the thresholds for ECG and angiography testing, and allow adequate monitoring of informative biomarkers. Moreover, the discovery of genetic markers associated with MI will provide novel targets for therapeutic intervention or preventive treatments of MI, and enable the development of new therapeutic agents for treating or preventing MI and other cardiovascular disorders.
• Furthermore, novel genetic markers that are predictive of predisposition to MI can be particularly useful for identifying individuals who are at risk for early-onset MI. “Early-onset MI” may be defined as MI in men who are less than 55 years of age and women who are less than 65 years of age. K. O. Akosah et al., “Preventing myocardial infarction in the young adult in the first place: How do the National Cholesterol Education Panel III guidelines perform?” JACC 41(9):1475-1479 (2003). Individuals who experience early-onset MI may not be effectively identified by current cholesterol treatment guidelines, such as those suggested by the National Cholesterol Education Program. In one study, for example, a significant number of individuals who suffered MI at an earlier age 50 years) were shown to have LDL cholesterol below 100 mg/dl. K. O. Akosah et al., “Myocardial infarction in young adults with low-density lipoprotein cholesterol levels less than or equal to 100 mg/dl. Clinical profile and 1-year outcomes.” Chest 120:1953-1958 (2001). Because risk for MI can be reduced by lifestyle changes and by treatment of modifiable risk factors, better methods to identify individuals at risk for early-onset MI could be useful for making preventive treatment decisions, especially considering that these patients may not be identified for medical management by conventional treatment guidelines. Genetic markers for risk of early-onset MI could potentially be incorporated into individual risk assessment protocols, as they have the advantage of being easily detected at any age.
• Hypertension
• Hypertension is a significant, modifiable risk factor for both CHD and stroke; two of the top three causes of mortality in the United States (Kearney et al., Lancet. 2005; 365:217-223; and Centers for Disease Control and Prevention, National Center for Health Statistics, FastStats). The prevalence of hypertension in US adults is estimated to be 29% (Ostchega et al., 2008, National Center for Health Statistics data brief no. 3), and the prevalence is expected to increase in the future (Kearney et al., Lancet. 2005; 365:217-223; and Hajjar et al., JAMA. 2003; 290:199-206). While about 5% of hypertension has known causes (classified as secondary hypertension), the majority of hypertension is due to unknown causes (classified as essential hypertension) (Cowley et al., Nature Reviews Genetics. 2006; 7:829-840). It is estimated that genetic variation contributes to between 30-60% of inter-individual blood pressure variation (Binder, Curr Opin Cardiol. 2007; 22:176-184) but the identity and nature of the contributing genetic loci are largely unknown.
• Statin Treatment
• HMG-CoA reductase inhibitors (statins) are used for the treatment and prevention of CVD, particularly MI. Reduction of MI and other coronary events and total mortality by treatment with HMG-CoA reductase inhibitors has been demonstrated in a number of randomized, double-blinded, placebo-controlled prospective trials. D. D. Waters, Clin Cardiol 24(8 Suppl):III3-7 (2001); B. K. Singh and J. L. Mehta, Curr Opin Cardiol 17(5):503-11 (2002). These drugs have their primary effect through the inhibition of hepatic cholesterol synthesis, thereby upregulating LDL receptors in the liver. The resultant increase in LDL catabolism results in decreased circulating LDL, a major risk factor for cardiovascular disease.
• Statins can be divided into two types according to their physicochemical and pharmacokinetic properties. Statins such as lovastatin, simvastatin, atorvastatin, and cerevastatin are lipophilic in nature and, as such, diffuse across membranes and thus are highly cell permeable. Hydrophilic statins such as pravastatin are more polar, such that they require specific cell surface transporters for cellular uptake. K. Ziegler and W. Stunkel, Biochim Biophys Acta 1139(3):203-9 (1992); M. Yamazaki et al., Am J Physiol 264(1 Pt 1):G36-44 (1993); T. Komai et al., Biochem Pharmacol 43(4):667-70 (1992). The latter statin utilizes a transporter, OATP2, whose tissue distribution is confined to the liver and, therefore, they are relatively hepato-specific inhibitors. B. Hsiang et al., J Biol Chem 274(52):37161-37168 (1999). The former statins, not requiring specific transport mechanisms, are available to all cells and they can directly impact a much broader spectrum of cells and tissues. These differences in properties may influence the spectrum of activities that each statin possesses. Pravastatin, for instance, has a low myopathic potential in animal models and myocyte cultures compared to lipophilic statins. B. A. Masters et al., Toxicol Appl Pharmacol 131(1):163-174 (1995); K. Nakahara et al., Toxicol Appl Pharmacol 152(1):99-106 (1998); J. C. Reijneveld et al., Pediatr Res 39(6):1028-1035 (1996).
• Evidence from gene association studies is accumulating to indicate that responses to drugs are, indeed, at least partly under genetic control. As such, pharmacogenetics—the study of variability in drug responses attributed to hereditary factors in different populations—may significantly assist in providing answers toward meeting this challenge. A. D. Roses, Nature 405(6788):857-865 (2000); V. Mooser et al., J Thromb Haemost 1(7):1398-1402 (2003); L. M. Humma and S. G. Terra, Am J Health Syst Pharm 59(13):1241-1252 (2002). Numerous associations have been reported between selected genotypes, as defined by SNPs and other genetic sequence variations, and specific responses to cardiovascular drugs. Polymorphisms in several genes have been suggested to influence responses to statins including CETP (J. A. Kuivenhoven et al., N Engl J Med 338(2):86-93 (1998)), beta-fibrinogen (M. P. de Maat et al., Arterioscler Thromb Vasc Biol 18(2):265-71 (1998)), hepatic lipase (A. Zambon et al., Circulation 103(6):792-798 (2001)), lipoprotein lipase (J. W. Jukema et al., Circulation 94(8):1913-1918 (1996)), glycoprotein IIIc (P. F. Bray et al., Am J Cardiol 88(4):347-352 (2001)), stromelysin-1 (M. P. de Maat et al., Am J Cardiol 83(6):852-856 (1999)), and apolipoprotein E (L. U. Gerdes et al., Circulation 101(12):1366-1371 (2000); J. Pedro-Botet et al., Atherosclerosis 158(1):183-193 (2001)). Some of these variants were shown to effect clinical events while others were associated with changes in surrogate endpoints.
• Thus, there is a need for genetic markers that can be used to predict an individual's responsiveness to statins. For example, there is a growing need to better identify people who have the highest chance of benefiting from statins, and those who have the lowest risk of developing side-effects. For example, severe myopathies represent a significant risk for a low percentage of the patient population, and this may be a particular concern for patients who are treated more aggressively with statins.
• Single Nucleotide Polymorphisms (SNPs)
• The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence gives rise to genetic polymorphisms, including SNPs.
• Approximately 90% of all genetic polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, SNP locus, SNP marker, or marker) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.
• A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an “indel.” Weber et al., “Human diallelic insertion/deletion polymorphisms,” Am J Hum Genet 71(4):854-62 (October 2002).
• A synonymous codon change, or silent mutation/SNP (terms such as “SNP,” “polymorphism,” “mutation,” “mutant,” “variation,” and “variant” are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e., a non-synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non-synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra-allelic, the vast majority of the SNPs are bi-allelic, and are thus often referred to as “bi-allelic markers,” or “di-allelic markers.”
• As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases. Stephens et al., Science 293:489-493 (July 2001).
• Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i.e., non-synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g., genetic disease. Examples of genes in which a SNP within a coding sequence causes a genetic disease include sickle cell anemia and cystic fibrosis.
• Causative SNPs do not necessarily have to occur in coding regions; causative SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disease-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disease. These SNPs, although not causative, are nonetheless also useful for diagnostics, disease predisposition screening, and other uses.
• An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as CVD, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as “healthy” or “normal” individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well-characterized phenotypes is extremely desirable.
• A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific pathological condition, such as pathologies related to CVD and in particular, CHD (particularly MI) and hypertension. Once a statistically significant association is established between one or more SNP(s) and a pathological condition (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene, regulatory region, etc.) that influences the pathological condition or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).
• Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed “pharmacogenomics”). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. Linder et al., Clinical Chemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al., Nature Biotechnology 16:3 (1998).
SUMMARY OF THE INVENTION
• The present invention relates to the identification of SNPs, as well as unique combinations of such SNPs and haplotypes of SNPs, that are associated with cardiovascular diseases (CVD), particularly coronary heart disease (CHD), especially myocardial infarction (MI), and hypertension. The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the diagnosis, prognosis, treatment, and/or prevention of CVD (particularly CHD, such as MI, and hypertension).
• Based on the identification of SNPs associated with CVD (particularly CHD, especially MI, and hypertension), the present invention also provides methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides, for example, SNPs associated with CVD, isolated nucleic acid molecules (including DNA and RNA molecules) containing these SNPs, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals who have an altered (i.e., increased or decreased) risk of developing CVD (particularly CHD, such as MI, and hypertension), methods for determining the risk of an individual for recurring CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), methods for prognosing the severity or consequences of CVD, methods of treating an individual who has an increased risk for CVD, and methods for identifying individuals (e.g., determining a particular individual's likelihood) who have an altered (i.e., increased or decreased) likelihood of responding to a drug treatment, particularly drug treatment of CVD (e.g., treatment or prevention of CHD, such as MI, or hypertension), based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNP sites disclosed herein or the detection of one or more encoded variant products (e.g., variant mRNA transcripts or variant proteins), methods of identifying individuals who are more or less likely to respond to a treatment such as statin treatment (or more or less likely to experience undesirable side effects from a treatment), methods of screening for compounds useful in the treatment or prevention of a disorder associated with a variant gene/protein, compounds identified by these methods, methods of treating or preventing disorders mediated by a variant gene/protein, methods of using the novel SNPs of the present invention for human identification, etc.
• The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer a treatment such as a statin to an individual having CVD, or who is at risk for developing CVD in the future, or who has previously had CVD, methods for selecting a particular treatment regimen such as dosage and frequency of administration of a therapeutic agent such as a statin, or a particular form/type of a therapeutic agent such as a particular pharmaceutical formulation or compound, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, etc. The present invention also provides methods for selecting individuals to whom a therapeutic agent (e.g., a statin) will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a therapeutic agent (e.g., a statin) based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively to the therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to the therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular therapeutic agent such as a statin based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them). The present invention further provides methods for reducing an individual's risk of developing CVD (such as CHD, particularly MI, and hypertension) using a drug treatment (e.g., statin treatment), including preventing recurring CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), when said individual carries one or more SNPs identified herein as being associated with CVD and/or response to statin treatment.
• In Tables 1 and 2, the present invention provides gene information, references to the identification of transcript sequences (SEQ ID NOS:1-307), encoded amino acid sequences (SEQ ID NOS:308-614), genomic sequences (SEQ ID NOS:1015-1400), transcript-based context sequences (SEQ ID NOS:615-1014) and genomic-based context sequences (SEQ ID NOS:1401-4006 and 5414) that contain the SNPs of the present invention, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The actual transcript sequences (SEQ ID NOS:1-307), amino acid sequences (SEQ ID NOS:308-614), genomic sequences (SEQ ID NOS:1015-1400), transcript-based SNP context sequences (SEQ ID NOS:615-1014), and genomic-based SNP context sequences (SEQ ID NOS:1401-4006 and 5414), together with primer sequences (SEQ ID NOS:4007-5413 and 5415-5416) are provided in the Sequence Listing.
• In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered risk for developing CVD, such as CHD (particularly MI) or hypertension (including, for example, a first incidence and/or a recurrence of the disease), in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-307, SEQ ID NOS:615-1014, SEQ ID NOS:1015-1400, and SEQ ID NOS:1401-4006 and 5414 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and/or Table 2, and the presence of the SNP is indicative of an altered risk for CVD in said individual. In certain embodiments, the CVD is CHD (particularly MI) or hypertension. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided as isolated nucleic acid molecules. These SNPs are associated with CVD (particular CHD, especially MI, and hypertension) such that they can have a variety of uses in the diagnosis, prognosis, treatment, and/or prevention of CVD and related pathologies. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.
• In yet another embodiment of the invention, a reagent for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) is provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment.
• Various embodiments of the invention also provide kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing detection reagents. In a specific embodiment, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing CVD (e.g., CHD, particularly MI, or hypertension) by detecting the presence or absence of one or more SNP alleles disclosed herein. In another embodiment, a method for diagnosis of CVD by detecting the presence or absence of one or more SNP alleles disclosed herein is provided. The present invention also provides methods for evaluating whether an individual is likely (or unlikely) to respond to a treatment (e.g., a therapeutic agent such as a statin) by detecting the presence or absence of one or more SNP alleles disclosed herein.
• The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents or pharmaceutical compounds useful in the treatment or prevention of CVD (particularly CHD, such as MI, or hypertension).
• An aspect of this invention is a method for treating or preventing CVD, such as CHD (particularly MI) or hypertension (including, for example, a first occurrence and/or a recurrence of the disease), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agent(s) counteracting the effects of the disease, such as by inhibiting (or stimulating) the activity of a gene, transcript, and/or encoded protein identified in Tables 1 and 2. In certain exemplary embodiments, the agent(s) comprise a statin.
• Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating CVD (particularly CHD, such as MI, or hypertension), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.
• Another aspect of this invention is a method for treating or preventing CVD (such as CHD, particularly MI, or hypertension), in a human subject, in which the method comprises:
• (i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, and
• (ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents (e.g., one or more statins) counteracting the effects of the disease.
• Another aspect of the invention is a method for identifying a human who is likely to benefit from a treatment (e.g., a therapeutic agent, particularly a statin), in which the method comprises detecting an allele of one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele indicates that said human is likely to benefit from the treatment.
• Another aspect of the invention is a method for identifying a human who is likely to benefit from a treatment (e.g., a therapeutic agent, particularly a statin), in which the method comprises detecting an allele of one or more SNPs that are in LD with one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele of the LD SNP indicates that said human is likely to benefit from the treatment.
• Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the preferred embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.
• Description of the Text (ASCII) File Submitted Electronically via EFS-Web
• The following text (ASCII) files are submitted electronically via EFS-Web as part of the instant application:
• 1) File SEQLIST_CD26ORD.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:1-307) and protein sequences (SEQ ID NOS:308-614) as referred to in Table 1, and genomic sequences (SEQ ID NOS:1015-1400) as referred to in Table 2, for each CVD-associated gene (or genomic region for intergenic SNPs) that contains one or more SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as referred to in Table 1 (SEQ ID NOS:615-1014) and genomic-based context sequences as referred to in Table 2 (SEQ ID NOS:1401-4006 and 5414). In addition, the Sequence Listing provides the primer sequences from Table 5 (SEQ ID NOS:4007-5413 and 5415-5416). The context sequences generally provide 100 bp upstream (5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middle of the context sequence, for a total of 200 bp of context sequence surrounding each SNP. File SEQLIST_CD26ORD.txt is 52,636 KB in size, and was created on Jul. 8, 2009.

• LENGTHY TABLES
  The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20230100271A1). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

• 2) File TABLE1_CD26ORD.txt provides Table 1, which is 477 KB in size, and was created on Jul. 7, 2009.
• 3) File TABLE2_CD26ORD.txt provides Table 2, which is 1,961 KB in size, and was created on Jul. 8, 2009.
• 4) File TABLE3_CD26ORD.txt provides Table 3, which is 1 KB in size, and was created on Jul. 6, 2009.
• 5) File TABLE4_CD26ORD.txt provides Table 4, which is 1 KB in size, and was created on Jul. 6, 2009.
• These text files are hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).
• Description of Table 1 and Table 2
• Table 1 and Table 2 (both submitted electronically via EFS-Web) disclose the SNP and associated gene/transcript/protein information of the present invention. For each gene, Table 1 provides a header containing gene, transcript and protein information, followed by a transcript and protein sequence identifier (SEQ ID NO), and then SNP information regarding each SNP found in that gene/transcript including the transcript context sequence. For each gene in Table 2, a header is provided that contains gene and genomic information, followed by a genomic sequence identifier (SEQ ID NO) and then SNP information regarding each SNP found in that gene, including the genomic context sequence.
• Note that SNP markers may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences. In some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions. Additionally, in either Table 1 or 2 a “Related Interrogated SNP” may be listed following a SNP which is determined to be in LD with that interrogated SNP according to the given Power value. SNPs can be readily cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers and/or public rs identification numbers, and to the Sequence Listing based on their corresponding SEQ ID NOs.
• The gene/transcript/protein information includes:
• a gene number (1 through n, where n=the total number of genes in the Table),
• a gene symbol, along with an Entrez gene identification number (Entrez Gene database, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health)
• a gene name,
• an accession number for the transcript (e.g., RefSeq NM number, or a Celera hCT identification number if no RefSeq NM number is available) (Table 1 only),
• an accession number for the protein (e.g., RefSeq NP number, or a Celera hCP identification number if no RefSeq NP number is available) (Table 1 only),
• the chromosome number of the chromosome on which the gene is located,
• an OMIM (“Online Mendelian Inheritance in Man” database, Johns Hopkins University/NCBI) public reference number for the gene, and OMIM information such as alternative gene/protein name(s) and/or symbol(s) in the OMIM entry.
• Note that, due to the presence of alternative splice forms, multiple transcript/protein entries may be provided for a single gene entry in Table 1; i.e., for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.
• Following the gene/transcript/protein information is a transcript context sequence (Table 1), or a genomic context sequence (Table 2), for each SNP within that gene.
• After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as “Intergenic region:” followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (such SNPs are identified as “INTERGENIC” for SNP type).
• Note that the transcript, protein, and transcript-based SNP context sequences are all provided in the Sequence Listing. The transcript-based SNP context sequences are provided in both Table 1 and also in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in the Sequence Listing. The genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOs are indicated in Table 1 for the transcript-based context sequences (SEQ ID NOS:615-1014); SEQ ID NOs are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS:1401-4006 and 5414).
• The SNP information includes:
• Context sequence (taken from the transcript sequence in Table 1, the genomic sequence in Table 2) with the SNP represented by its IUB code, including 100bp upstream (5′) of the SNP position plus 100bp downstream (3′) of the SNP position (the transcript-based SNP context sequences in Table 1 are provided in the Sequence Listing as SEQ ID NOS:615-1014; the genomic-based SNP context sequences in Table 2 are provided in the Sequence Listing as SEQ ID NOS:1401-4006 and 5414).
• Celera hCV internal identification number for the SNP (in some instances, an “hDV” number is given instead of an “hCV” number; “hDV68873046” may be interchangeably referred to herein as “hCV29714327”).
• The corresponding public identification number for the SNP, the rs number.
• “SNP Chromosome Position” indicates the nucleotide position of the SNP along the entire sequence of the chromosome as provided in NCBI Genome Build 36.
• SNP position (nucleotide position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)).
• “Related Interrogated SNP” is the interrogated SNP with which the listed SNP is in LD at the given value of Power.
• SNP source (may include any combination of one or more of the following five codes, depending on which internal sequencing projects and/or public databases the SNP has been observed in: “Applera”=SNP observed during the re-sequencing of genes and regulatory regions of 39 individuals, “Celera”=SNP observed during shotgun sequencing and assembly of the Celera human genome sequence, “Celera Diagnostics”=SNP observed during re-sequencing of nucleic acid samples from individuals who have a disease, “dbSNP”=SNP observed in the dbSNP public database, “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD) public database, “HapMap”=SNP observed in the International HapMap Project public database, “CSNP”=SNP observed in an internal Applied Biosystems (Foster City, Calif.) database of coding SNPS (cSNPs).
• Note that multiple “Applera” source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re-sequencing results (e.g., observed allele counts) from each of these amplification products is being provided.
• Population/allele/allele count information in the format of [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count) total (first_allele,total count|second_allele,total count)]. The information in this field includes populations/ethnic groups in which particular SNP alleles have been observed (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and “afr”=African-American, “jpn”=Japanese, “ind”=Indian, “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor, “no_pop”=no population information available), identified SNP alleles, and observed allele counts (within each population group and total allele counts), where available [−-” in the allele field represents a deletion allele of an insertion/deletion (“indel”) polymorphism (in which case the corresponding insertion allele, which may be comprised of one or more nucleotides, is indicated in the allele field on the opposite side of the “|”); “-” in the count field indicates that allele count information is not available]. For certain SNPs from the public dbSNP database, population/ethnic information is indicated as follows (this population information is publicly available in dbSNP): “HISP1”=human individual DNA (anonymized samples) from 23 individuals of self-described HISPANIC heritage; “PAC1”=human individual DNA (anonymized samples) from 24 individuals of self-described PACIFIC RIM heritage; “CAUC1”=human individual DNA (anonymized samples) from 31 individuals of self-described CAUCASIAN heritage; “AFR1”=human individual DNA (anonymized samples) from 24 individuals of self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human individual DNA (anonymized samples) from 102 individuals of self-described heritage; “PA130299515”; “SC_12_A”=SANGER 12 DNAs of Asian origin from Corielle cell repositories, 6 of which are male and 6 female; “SC_12_C”=SANGER 12 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library, six male and six female; “SC_12_AA”=SANGER 12 DNAs of African-American origin from Corielle cell repositories 6 of which are male and 6 female; “SC_95_C”=SANGER 95 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library; and “SC_12_CA”=Caucasians—12 DNAs from Corielle cell repositories that are from the CEPH/UTAH library, six male and six female.
• Note that for SNPs of “Applera” SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African-American (“afr”) allele counts is up to 38, the sum of the Caucasian allele counts (“cau”) is up to 40, and the total sum of all allele counts is up to 78.
• Note that semicolons separate population/allele/count information corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the corresponding listing of population/allele/count information.
• SNP type (e.g., location within gene/transcript and/or predicted functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in the encoded amino acid (i.e., a non-synonymous coding SNP); “SILENT MUTATION”=SNP does not cause a change in the encoded amino acid (i.e., a synonymous coding SNP); “STOP CODON MUTATION”=SNP is located in a stop codon; “NONSENSE MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a 3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative 3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located in an acceptor splice site (3′ intron boundary); “CODING REGION”=SNP is located in a protein-coding region of the transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is located in an intron; “hmCS”=SNP is located in a human-mouse conserved segment; “TFBS”=SNP is located in a transcription factor binding site; “UNKNOWN”=SNP type is not defined; “INTERGENIC”=SNP is intergenic, i.e., outside of any gene boundary].
• Protein coding information (Table 1 only), where relevant, in the format of [protein SEQ ID NO, amino acid position, (amino acid-1, codon1) (amino acid-2, codon2)]. The information in this field includes SEQ ID NO of the encoded protein sequence, position of the amino acid residue within the protein identified by the SEQ ID NO that is encoded by the codon containing the SNP, amino acids (represented by one-letter amino acid codes) that are encoded by the alternative SNP alleles (in the case of stop codons, “X” is used for the one-letter amino acid code), and alternative codons containing the alternative SNP nucleotides which encode the amino acid residues (thus, for example, for missense mutation-type SNPs, at least two different amino acids and at least two different codons are generally indicated; for silent mutation-type SNPs, one amino acid and at least two different codons are generally indicated, etc.). In instances where the SNP is located outside of a protein-coding region (e.g., in a UTR region), “None” is indicated following the protein SEQ ID NO.
• Note that SNPs can be cross-referenced between any of Tables 1-22 herein based on their hCV and/or rs identification numbers. However, two of the SNPs that are included in the tables may possess two different hCV identification numbers, as follows:
• SNP hCV25473098 is the same as SNP hCV16173091 set forth in Tables 1-2.
• SNP hCV16192174 is the same as SNP hCV22271999 set forth in Tables 1-2.
• SNP hCV25640504 can be represented by either genomic context sequences SEQ ID
• NOS:2554 or 5414 (each of which is set forth in Table 2 and the Sequence Listing), and can be assayed using either allele-specific primers SEQ ID NOS:4580-4581 or SEQ ID NOS:5415-5416 (any of which can be used in combination with common primer SEQ ID NO:4582) (each of which allele-specific and common primers is set forth in Table 5 and the Sequence Listing).
• Description of Table 3 and Table 4
• Tables 3 and 4 (both submitted electronically via EFS-Web) provide a list of a subset of SNPs from Table 1 (in the case of Table 3) or Table 2 (in the case of Table 4) for which the SNP source falls into one of the following three categories: 1) SNPs for which the SNP source is only “Applera” and none other, 2) SNPs for which the SNP source is only “Celera Diagnostics” and none other, and 3) SNPs for which the SNP source is both “Applera” and “Celera Diagnostics” but none other.
• These SNPs have not been observed in any of the public databases (dbSNP, HGBASE, and HGMD), and were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., “Celera” SNP source). Tables 3 and 4 provide the hCV identification number (or hDV identification number for SNPs having “Celera Diagnostics” SNP source) and the SEQ ID NO of the context sequence for each of these SNPs.
• Description of Table 5
• Table 5 provides sequences (SEQ ID NOS:4007-5413 and 5415-5416) of primers that may be used to assay the SNPs disclosed herein by allele-specific PCR or other methods, such as for uses related to CVD.
• Table 5 provides the following:
• the column labeled “Marker” provides an hCV identification number for each SNP that can be detected using the corresponding primers.
• the column labeled “Alleles” designates the two alternative alleles (i.e., nucleotides) at the SNP site. These alleles are targeted by the allele-specific primers (the allele-specific primers are shown as Primer 1 and Primer 2). Note that alleles may be presented in Table 5 based on a different orientation (i.e., the reverse complement) relative to how the same alleles are presented in Tables 1-2.
• the column labeled “Primer 1 (Allele-Specific Primer)” provides an allele-specific primer that is specific for an allele designated in the “Alleles” column.
• the column labeled “Primer 2 (Allele-Specific Primer)” provides an allele-specific primer that is specific for the other allele designated in the “Alleles” column.
• the column labeled “Common Primer” provides a common primer that is used in conjunction with each of the allele-specific primers (i.e., Primer 1 and Primer 2) and which hybridizes at a site away from the SNP position.
• All primer sequences are given in the 5′ to 3′ direction.
• Each of the nucleotides designated in the “Alleles” column matches or is the reverse complement of (depending on the orientation of the primer relative to the designated allele) the 3′ nucleotide of the allele-specific primer (i.e., either Primer 1 or Primer 2) that is specific for that allele.
• Description of Table 6
• Table 6 provides a list of LD SNPs that are related to and derived from certain interrogated SNPs. The interrogated SNPs, which are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 6, are statistically significantly associated with CVD, as described and shown herein, particularly in Tables 7-22 and in the Examples section below. The LD SNPs are provided as an example of SNPs which can also serve as markers for disease association based on their being in LD with an interrogated SNP. The criteria and process of selecting such LD SNPs, including the calculation of the r² value and the r² threshold value, are described in Example 6, below.
• In Table 6, the column labeled “Interrogated SNP” presents each marker as identified by its unique hCV identification number. The column labeled “Interrogated rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “LD SNP” presents the hCV numbers of the LD SNPs that are derived from their corresponding interrogated SNPs. The column labeled “LD SNP rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “Power” presents the level of power where the r² threshold is set. For example, when power is set at 0.51, the threshold r² value calculated therefrom is the minimum r² that an LD SNP must have in reference to an interrogated SNP, in order for the LD SNP to be classified as a marker capable of being associated with a disease phenotype at greater than 51% probability. The column labeled “Threshold r²” presents the minimum value of r² that an LD SNP must meet in reference to an interrogated SNP in order to qualify as an LD SNP. The column labeled “r²” presents the actual r² value of the LD SNP in reference to the interrogated SNP to which it is related.
• Description of Tables 7-22
• Tables 7-22 provide the results of statistical analyses for SNPs disclosed in Tables 1 and 2 (SNPs can be cross-referenced between all the tables herein based on their hCV and/or rs identification numbers). The results shown in Tables 7-22 provide support for the association of these SNPs with CVD, particularly CHD (especially MI) and/or hypertension.
• Table 7 provides association test results from two MI case-control studies (see Example 1 below).
• Table 8 provides descriptive information by race and GOSR2 genotype (see Example 1 below).
• Table 9 provides OR and 95% CI for the association between GOSR2 (Lys67Arg, rs197922), hypertension, and carotid artery thickness (see Example 1 below).
• Table 10 provides SNPs surrounding GOSR2 SNP rs197922 (hCV2275273) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).
• Table 11 provides risk factors for MI in participants of three case-control studies (see Example 2 below).
• Table 12 provides twenty-four SNPs associated with MI in Study 1 (UCSF) and Study 2 (UCSF) (see Example 2 below).
• Table 13 provides results for genotypic association of five SNPs in Study 3 (CCF) (see Example 2 below).
• Table 14 provides SNPs surrounding the ENO1 SNP rs1325920 (hCV8824241) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).
• Table 15 provides SNPs surrounding the FXN SNP rs10890 (hCV1463226) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).
• Table 16 provides SNPs surrounding the RERE SNP rs10779705 (hCV32055477) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).
• Table 17 provides SNPs surrounding VAMP8 rs1010 (hCV2091644) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).
• Tables 18 and 19 provide SNPs surrounding the LPA SNP rs3798220 (hCV25930271) that are associated with CVD, particularly CHD, and especially MI. Table 18 provides results of an analysis of the UCSF1 sample set, and Table 19 provides results of a meta-analysis of the UCSF1 and UCSF2 sample sets combined. The SNPs provided in Table 19 are also associated with Lp(a) levels (see Example 3 below).
• Table 20 provides SNPs (from a functional genome scan (FGS)) associated with CVD, particularly CHD, and especially MI, in two studies (see Example 4 below).
• Table 21 provides SNPs associated with reduction of CHD risk, particularly risk for MI and recurrent MI, by Pravastatin in the CARE study, and Table 22 provides SNPs associated with risk of CHD, particularly risk for MI and recurrent MI, in the placebo arm of the CARE study. The SNPs provided in Table 22 are a subset of the SNPs provided in Table 21; thus, the SNPs provided in Table 22 are associated with both increased CHD risk as well as reduction of CHD risk by statin treatment (e.g., Pravastatin) (see Example 5 below).
• Table 21 provides SNPs for which the effect of pravastatin on the primary endpoint of the CARE study (identified as “endptl” in the Endpoint column) or the recurrent MI endpoint (identified as “rmi” in the Endpoint column) was analyzed by genotype subgroups and for which pravastatin reduced risk in one genotype subgroup but not in another (P-interaction between statin treatment and genotype for the enpdpoint<0.1).
• Table 22 provides a subset of SNPs from Table 21 that were associated (p<0.1) with time to occurrence of first event, either the CARE primary endpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebo group of the CARE study. In Table 22, the HR (including lower and upper confidence intervals) and p-values indicated for each SNP correspond to Allele 1 (Allele 2 is the reference allele, which is considered to have HR=1).
• In Tables 21-22, the column labeled “Endpoint” indicates whether the endpoint that was analyzed was the primary endpoint of the CARE study (a composite endpoint of fatal coronary event or nonfatal MI, and identified as “endpt1”) or a composite endpoint of confirmed fatal or nonfatal MI (identified as “rmi”). Also in Tables 21-22, the column labeled “Events” indicates the number of individuals in the CARE study who had an event (a fatal coronary event or nonfatal MI if “endpt1” is indicated in the Endpoint column, or a fatal or nonfatal MI if “rmi” is indicated in the Endpoint column). Table 22 indicates, for each SNP, the number of individuals in the placebo arm of the CARE study who had an event (column labeled “Events (placebo arm)”) and the total number of individuals (column labeled “Total Patients (placebo arm)”). Table 21 indicates, for each SNP, the number of individuals who had an event in each of the Pravastatin and placebo arms of the CARE study (columns labeled “Events (Pravastatin arm)” and “Events (placebo arm)”, respectively) and the number of individuals who did not have an event in each of the Pravastatin and placebo arms of the CARE study (columns labeled “Nonevent (Pravastatin arm)” and “Nonevent (placebo arm)”, respectively).
• Throughout Tables 7-22, with respect to model, “add” is additive, “rec” is recessive, “dom” is dominant, “het” is heterozygotes compared with reference homozygotes, and “hom” is non-reference homozygotes compared with reference homozygotes, and with respect to strata, “M” is males only and “F” is females only.
• Throughout Tables 7-22, “OR” refers to the odds ratio, “HR” refers to the hazard ratio, and “90% CI” or “95% CI” refers to the 90% or 95% confidence interval (respectively) for the odds ratio or hazard ratio (“OR95U” and “OR95L” refer to the upper and lower 95% confidence intervals, respectively, for the odds ratio; and “HR95U” and “HR95L” refer to the upper and lower 95% confidence intervals, respectively, for the hazard ratio). Odds ratios (OR) or hazard ratios (HR) that are greater than one indicate that a given allele is a risk allele (which may also be referred to as a susceptibility allele), whereas odds ratios that are less than one indicate that a given allele is a non-risk allele (which may also be referred to as a protective allele). For a given risk allele, the other alternative allele at the SNP position (which can be derived from the information provided in Tables 1-2, for example) may be considered a non-risk allele. For a given non-risk allele, the other alternative allele at the SNP position may be considered a risk allele.
• Thus, with respect to disease risk (e.g., CVD such as CHD, particularly MI, or hypertension), if the risk estimate (odds ratio or hazard ratio) for a particular allele at a SNP position is greater than one, this indicates that an individual with this particular allele has a higher risk for the disease than an individual who has the other allele at the SNP position. In contrast, if the risk estimate (odds ratio or hazard ratio) for a particular allele is less than one, this indicates that an individual with this particular allele has a reduced risk for the disease compared with an individual who has the other allele at the SNP position.
• With respect to drug response (e.g., response to a statin), if the risk estimate (odds ratio or hazard ratio) of those treated with the drug (e.g., a statin) compared with those treated with a placebo within a particular genotype is less than one, this indicates that an individual with this particular genotype would benefit from the drug (an odds ratio or hazard ratio equal to one would indicate that the drug has no effect). As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment) is defined as achieving a reduced risk for a disease that the drug is intended to treat or prevent (e.g., CVD such as CHD, particularly MI, or hypertension) by administering the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype.
DETAILED DESCRIPTION OF THE INVENTION
• The present invention provides SNPs associated with cardiovascular diseases (CVD), particularly coronary heart disease (CHD), especially myocardial infarction (MI), and hypertension. The present invention further provides nucleic acid molecules containing these SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The SNPs disclosed herein are useful for diagnosing, prognosing, screening for, and evaluating predisposition to CVD and related pathologies in humans. The SNPs disclosed herein may also be used for predicting, screening for, and evaluating response to a treatment (e.g., a therapeutic agent, particularly a statin), particularly treatment or prevention of CVD, in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic and preventive agents.
• A large number of SNPs have been identified from re-sequencing DNA from 39 individuals, and they are indicated as “Applera” SNP source in Tables 1-2. Their allele frequencies observed in each of the Caucasian and African-American ethnic groups are provided. Additional SNPs included herein were previously identified during “shotgun” sequencing and assembly of the human genome, and they are indicated as “Celera” SNP source in Tables 1 and 2. Furthermore, the information provided in Tables 1 and 2, particularly the allele frequency information obtained from 39 individuals and the identification of the precise position of each SNP within each gene/transcript, allows haplotypes (i.e., groups of SNPs that are co-inherited) to be readily inferred. The present invention encompasses SNP haplotypes, as well as individual SNPs.
• Thus, the present invention provides individual SNPs associated with CVD (particularly CHD, especially MI, and hypertension), as well as combinations of SNPs and haplotypes, polymorphic/variant transcript sequences (SEQ ID NOS:1-307) and genomic sequences (SEQ ID NOS:1015-1400) containing SNPs, encoded amino acid sequences (SEQ ID NOS:308-614), and both transcript-based SNP context sequences (SEQ ID NOS:615-1014) and genomic-based SNP context sequences (SEQ ID NOS:1401-4006 and 5414) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing CVD, methods of determining if an individual is likely to respond to a particular treatment such as a therapeutic agent such as a statin (particularly for treating or preventing CVD), methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as CVD, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment/preventive strategy or therapeutic agent, methods of treating or preventing a disorder associated with a variant gene/protein, and methods of using the SNPs of the present invention for human identification.
• The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer a therapeutic agent, particularly a statin, to an individual having CVD, or who is at risk for developing CVD in the future, or who has previously had CVD, methods for selecting a particular treatment regimen such as dosage and frequency of administration of a therapeutic agent (e.g., a statin), or a particular form/type of a therapeutic agent such as a particular pharmaceutical formulation or compound, methods for administering an alternative treatment to individuals who are predicted to be unlikely to respond positively to a particular treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, etc. The present invention also provides methods for selecting individuals to whom a therapeutic agent (e.g., a statin) will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a therapeutic agent (e.g., a statin) based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively to a therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to a therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular agent such as a statin based on their SNP genotype(s) to participate in a clinical trial of another thereapeutic agent that may benefit them).
• The present invention may include novel SNPs associated with CVD and/or statin response, as well as SNPs that were previously known in the art, but were not previously known to be associated with CVD and/or statin response. Accordingly, the present invention may provide novel compositions and methods based on novel SNPs disclosed herein, and may also provide novel methods of using known, but previously unassociated, SNPs in methods relating to, for example, evaluating an individual's likelihood of having or developing CVD (particularly CHD, such as MI, and hypertension), predicting the likelihood of an individual experiencing a reccurrence of CVD (e.g., experiencing recurrent CHD, particularly recurrent MI, or recurrent hypertension), prognosing the severity of CVD in an individual, or prognosing an individual's recovery from CVD, and methods relating to evaluating an individual's likelihood of responding to a treatment such as a particular therapeutic agent, especially a statin (particularly for treatment, including preventive treatment, of CVD). In Tables 1 and 2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: “dbSNP”=SNP observed in dbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD).
• Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) or increased likelihood of responding to a treatment such as a statin (particularly treatment, including preventive treatment, of CVD), or a decreased risk of having or developing CVD or decreased likelihood of responding to a treatment. Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) or increased likelihood of responding to a treatment, other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing CVD or decreased likelihood of responding to a treatment. Similarly, particular SNP alleles of the present invention can be associated with either an increased or decreased likelihood of having a reccurrence of CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), of fully recovering from CVD, of experiencing toxic effects from a particular treatment or therapeutic compound, etc. The term “altered” may be used herein to encompass either of these two possibilities (e.g., an increased or a decreased risk/likelihood). SNP alleles that are associated with a decreased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) may be referred to as “protective” alleles, and SNP alleles that are associated with an increased risk of having or developing CVD may be referred to as “susceptibility” alleles, “risk” alleles, or “risk factors”.
• Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.
• References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the “wild-type,” “reference,” or “normal” protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e., a missense mutation) disclosed by the present invention. Variant peptides/polypeptides/proteins of the present invention can also result from a nonsense mutation (i.e., a SNP that creates a premature stop codon, a SNP that generates a read-through mutation by abolishing a stop codon), or due to any SNP disclosed by the present invention that otherwise alters the structure, function, activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably.
• As used herein, an “allele” may refer to a nucleotide at a SNP position (wherein at least two alternative nucleotides are present in the population at the SNP position, in accordance with the inherent definition of a SNP) or may refer to an amino acid residue that is encoded by the codon which contains the SNP position (where the alternative nucleotides that are present in the population at the SNP position form alternative codons that encode different amino acid residues). An “allele” may also be referred to herein as a “variant”. Also, an amino acid residue that is encoded by a codon containing a particular SNP may simply be referred to as being encoded by the SNP.
• A phrase such as “as represented by”, “as shown by”, “as symbolized by”, or “as designated by” may be used herein to refer to a SNP within a sequence (e.g., a polynucleotide context sequence surrounding a SNP), such as in the context of “a polymorphism as represented by position 101 of SEQ ID NO:X or its complement”. Typically, the sequence surrounding a SNP may be recited when referring to a SNP, however the sequence is not intended as a structural limitation beyond the specific SNP position itself. Rather, the context sequence is recited merely as a way of referring to the SNP (in this example, “SEQ ID NO:X or its complement” is recited in order to refer to the SNP located at position 101 of SEQ ID NO:X, but SEQ ID NO:X or its complement is not intended as a structural limitation beyond the specific SNP position itself). In other words, it is recognized that the context sequence of SEQ ID NO:X in this example may contain one or more polymorphic nucleotide positions outside of position 101 and therefore an exact match over the full-length of SEQ ID NO:X is irrelevant since SEQ ID NO:X is only meant to provide context for referring to the SNP at position 101 of SEQ ID NO:X. Likewise, the length of the context sequence is also irrelevant (100 nucleotides on each side of a SNP position has been arbitrarily used in the present application as the length for context sequences merely for convenience and because 201 nucleotides of total length is expected to provide sufficient uniqueness to unambiguously identify a given nucleotide sequence). Thus, since a SNP is a variation at a single nucleotide position, it is customary to refer to context sequence (e.g., SEQ ID NO:X in this example) surrounding a particular SNP position in order to uniquely identify and refer to the SNP. Alternatively, a SNP can be referred to by a unique identification number such as a public “rs” identification number or an internal “hCV” identification number, such as provided herein for each SNP (e.g., in Tables 1-2).
• As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment such as a statin) is defined as achieving a reduced risk for a disease that the drug (e.g., statin) is intended to treat or prevent (e.g., CVD such as CHD, particularly MI, and hypertension) by administrating the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype. The term “benefit” may be used herein interchangeably with terms such as “respond positively” or “positively respond”.
• As used herein, the terms “drug” and “therapeutic agent” are used interchangeably, and may include, but are not limited to, small molecule compounds, biologics (e.g., antibodies, proteins, protein fragments, fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc., which may be used for therapeutic and/or preventive treatment of a disease (e.g., CVD such as CHD, particularly MI, or hypertension).
• As used herein, a “drug” , “therapeutic agent”, or “treatment”, may include any agent used in the treatment (including therapeutic or preventive treatment) of CVD, particularly CHD (e.g., MI) or hypertension, such as, for example, a statin such as pravastatin (Pravachol®), atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®), rosuvastatin (Crestor®), simvastatin (Zocor®), and storvastatin, as well as combination therapies that include a statin such as simvastatin+ezetimibe (Vytorin®), lovastatin+niacin extended-release (Advicor®), and atorvastatin+amlodipine besylate (Caduet®).
• Hormone Replacement Therapy (HRT)
• Certain aspects of the invention relate to methods of using SNP rs3798220 (which is also referred to herein as hCV25930271) for utilities related to hormone replacement therapy (HRT), particularly methods that relate to carriers of the rs3798220 risk allele (C) benefiting from hormone replacement therapy.
• SNP rs3798220, which is in the LPA gene, is associated with risk of CVD, particularly MI (as described herein, particularly in Example 2 below; also see Luke et al. ATVB 2007; 27:2030-2036, which is incorporated herein by reference in its entirety). SNP rs3798220 is also associated with Lp(a) levels. Shilpak et al. (JAMA. 2000; 283:1845) have shown in the HERS study that women in the hormone replacement therapy (estrogen+progestin treatment) group with high baseline Lp(a) have significant reduction of cardiovascular events compared with placebo. About 70% of carriers of the rs3798220 risk allele (C) have very high Lp(a) levels.
• Accordingly, certain exemplary embodiments of the invention provide methods of using SNP rs3798220 (hCV25930271) for utilities related to HRT, such as methods of determining whether an individual will benefit from HRT based on which allele the individual possesses at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be identified as an individual who would benefit from HRT), methods of determining an individual's risk for CVD (particularly cardiovascular events such as MI) following HRT based on which allele the individual possesses at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be identified as an individual who would have a reduced risk for cardiovascular events such as MI following HRT as compared to the individual's risk for cardiovascular events in the absence of HRT (e.g., as compared with placebo)), and methods of treating an individual with HRT based on having identified that individual as someone who would be predicted to benefit from HRT (e.g., have a reduced risk for CVD, particularly cardiovascular events such as MI, following HRT) based on which allele they possess at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be treated with HRT, since it would therefore be predicted that the individual would benefit from HRT), as well as other related methods.
• Reports, Programmed Computers, Business Methods, and Systems
• The results of a test (e.g., an individual's risk for CVD such as CHD, particularly MI, or hypertension), or an individual's predicted drug responsiveness (e.g., response to statin treatment), based on assaying one or more SNPs disclosed herein, and/or an individual's allele(s)/genotype at one or more SNPs disclosed herein, etc.), and/or any other information pertaining to a test, may be referred to herein as a “report”. A tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as “reporting”, or as “providing” a report, “producing” a report, or “generating” a report).
• Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a “secure database” that has security features that limit access to the report, such as to allow only the patient and the patient's medical practioners to view the report while preventing other unauthorized individuals from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).
• A report can include, for example, an individual's risk for CVD, such as CHD (e.g., MI) or hypertension, or may just include the allele(s)/genotype that an individual carries at one or more SNPs disclosed herein, which may optionally be linked to information regarding the significance of having the allele(s)/genotype at the SNP (for example, a report on computer readable medium such as a network server may include hyperlink(s) to one or more journal publications or websites that describe the medical/biological implications, such as increased or decreased disease risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include disease risk or other medical/biological significance (e.g., drug responsiveness, etc.) as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including disease risk or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated disease risk or other medical/biological significance from a source outside of the report itself, such as from a medical practioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink).
• A report can further be “transmitted” or “communicated” (these terms may be used herein interchangeably), such as to the individual who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report. The act of “transmitting” or “communicating” a report can be by any means known in the art, based on the format of the report. Furthermore, “transmitting” or “communicating” a report can include delivering a report (“pushing”) and/or retrieving (“pulling”) a report. For example, reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically or in signal form (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server, etc.
• In certain exemplary embodiments, the invention provides computers (or other apparatus/devices such as biomedical devices or laboratory instrumentation) programmed to carry out the methods described herein. For example, in certain embodiments, the invention provides a computer programmed to receive (i.e., as input) the identity (e.g., the allele(s) or genotype at a SNP) of one or more SNPs disclosed herein and provide (i.e., as output) the disease risk (e.g., an individual's risk for CVD such as CHD, particularly MI, or hypertension) or other result (e.g., disease diagnosis or prognosis, drug responsiveness, etc.) based on the identity of the SNP(s). Such output (e.g., communication of disease risk, disease diagnosis or prognosis, drug responsiveness, etc.) may be, for example, in the form of a report on computer readable medium, printed in paper form, and/or displayed on a computer screen or other display.
• In various exemplary embodiments, the invention further provides methods of doing business (with respect to methods of doing business, the terms “individual” and “customer” are used herein interchangeably). For example, exemplary methods of doing business can comprise assaying one or more SNPs disclosed herein and providing a report that includes, for example, a customer's risk for CVD such as CHD, particularly MI, or hypertension (based on which allele(s)/genotype is present at the assayed SNP(s)) and/or that includes the allele(s)/genotype at the assayed SNP(s) which may optionally be linked to information (e.g., journal publications, websites, etc.) pertaining to disease risk or other biological/medical significance such as by means of a hyperlink (the report may be provided, for example, on a computer network server or other computer readable medium that is internet-accessible, and the report may be included in a secure database that allows the customer to access their report while preventing other unauthorized individuals from viewing the report), and optionally transmitting the report. Customers (or another party who is associated with the customer, such as the customer's doctor, for example) can request/order (e.g., purchase) the test online via the internet (or by phone, mail order, at an outlet/store, etc.), for example, and a kit can be sent/delivered (or otherwise provided) to the customer (or another party on behalf of the customer, such as the customer's doctor, for example) for collection of a biological sample from the customer (e.g., a buccal swab for collecting buccal cells), and the customer (or a party who collects the customer's biological sample) can submit their biological samples for assaying (e.g., to a laboratory or party associated with the laboratory such as a party that accepts the customer samples on behalf of the laboratory, a party for whom the laboratory is under the control of (e.g., the laboratory carries out the assays by request of the party or under a contract with the party, for example), and/or a party that receives at least a portion of the customer's payment for the test). The report (e.g., results of the assay including, for example, the customer's disease risk and/or allele(s)/genotype at the assayed SNP(s)) may be provided to the customer by, for example, the laboratory that assays the SNP(s) or a party associated with the laboratory (e.g., a party that receives at least a portion of the customer's payment for the assay, or a party that requests the laboratory to carry out the assays or that contracts with the laboratory for the assays to be carried out) or a doctor or other medical practitioner who is associated with (e.g., employed by or having a consulting or contracting arrangement with) the laboratory or with a party associated with the laboratory, or the report may be provided to a third party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides the report to the customer. In further embodiments, the customer may be a doctor or other medical practitioner, or a hospital, laboratory, medical insurance organization, or other medical organization that requests/orders (e.g., purchases) tests for the purposes of having other individuals (e.g., their patients or customers) assayed for one or more SNPs disclosed herein and optionally obtaining a report of the assay results.
• In certain exemplary methods of doing business, a kit for collecting a biological sample (e.g., a buccal swab for collecting buccal cells, or other sample collection device) is provided to a medical practitioner (e.g., a physician) which the medical practitioner uses to obtain a sample (e.g., buccal cells, saliva, blood, etc.) from a patient, the sample is then sent to a laboratory (e.g., a CLIA-certified laboratory) or other facility that tests the sample for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the patient's risk for CVD such as CHD, particularly MI, or hypertension), and the results of the test (e.g., the patient's genotype at one or more SNPs disclosed herein and/or the patient's disease risk based on their SNP genotype) are provided back to the medical practitioner (and/or directly to the patient and/or to another party such as a hospital, medical insurance company, genetic counselor, etc.) who may then provide or otherwise convey the results to the patient. The results are typically provided in the form of a report, such as described above.
• In certain further exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells, or other sample collection device) are provided (e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy, general merchandise store, or any other desirable outlet), online via the internet, by mail order, etc., whereby customers can obtain (e.g., purchase) the kits, collect their own biological samples, and submit (e.g., send/deliver via mail) their samples to a laboratory (e.g., a CLIA-certified laboratory) or other facility which tests the samples for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the customer's risk for CVD such as CHD, particularly MI, or hypertension) and provides the results of the test (e.g., of the customer's genotype at one or more SNPs disclosed herein and/or the customer's disease risk based on their SNP genotype) back to the customer and/or to a third party (e.g., a physician or other medical practitioner, hospital, medical insurance company, genetic counselor, etc.). The results are typically provided in the form of a report, such as described above. If the results of the test are provided to a third party, then this third party may optionally provide another report to the customer based on the results of the test (e.g., the result of the test from the laboratory may provide the customer's genotype at one or more SNPs disclosed herein without disease risk information, and the third party may provide a report of the customer's disease risk based on this genotype result).
• Certain further embodiments of the invention provide a system for determining an individual's CVD risk (e.g., risk for CHD, particularly MI, or hypertension), or whether an individual will benefit from statin treatment (or other therapy) in reducing CVD risk. Certain exemplary systems comprise an integrated “loop” in which an individual (or their medical practitioner) requests a determination of such individual's CVD risk (or drug response, such as response to statin treatment, etc.), this determination is carried out by testing a sample from the individual, and then the results of this determination are provided back to the requestor. For example, in certain systems, a sample (e.g., buccal cells, saliva, blood, etc.) is obtained from an individual for testing (the sample may be obtained by the individual or, for example, by a medical practitioner), the sample is submitted to a laboratory (or other facility) for testing (e.g., determining the genotype of one or more SNPs disclosed herein), and then the results of the testing are sent to the patient (which optionally can be done by first sending the results to an intermediary, such as a medical practioner, who then provides or otherwise conveys the results to the individual and/or acts on the results), thereby forming an integrated loop system for determining an individual's CVD risk (or drug response, etc.). The portions of the system in which the results are transmitted (e.g., between any of a testing facility, a medical practitioner, and/or the individual) can be carried out by way of electronic or signal transmission (e.g., by computer such as via e-mail or the internet, by providing the results on a website or computer network server which may optionally be a secure database, by phone or fax, or by any other wired or wireless transmission methods known in the art). Optionally, the system can further include a risk reduction component (i.e., a disease management system) as part of the integrated loop (for an example of a disease management system, see U.S. Pat. No. 6,770,029, “Disease management system and method including correlation assessment”). For example, the results of the test can be used to reduce the risk of the disease in the individual who was tested, such as by implementing a preventive therapy regimen (e.g., administration of a drug regimen such as a statin treatment for reducing CVD risk), modifying the individual's diet, increasing exercise, reducing stress, and/or implementing any other physiological or behavioral modifications in the individual with the goal of reducing disease risk. For reducing CVD risk (e.g., risk for CHD, particularly MI, or hypertension), this may include any means used in the art for improving aspects of an individual's health relevant to reducing CVD risk. Thus, in exemplary embodiments, the system is controlled by the individual and/or their medical practioner in that the individual and/or their medical practioner requests the test, receives the test results back, and (optionally) acts on the test results to reduce the individual's disease risk, such as by implementing a disease management system.
• The various methods described herein, such as correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for CVD such as CHD, particularly MI, or hypertension (and/or correlating the presence or absence of a polymorphism with the predicted response of an individual to a drug such as a statin), can be carried out by automated methods such as by using a computer (or other apparatus/devices such as biomedical devices, laboratory instrumentation, or other apparatus/devices having a computer processor) programmed to carry out any of the methods described herein. For example, computer software (which may be interchangeably referred to herein as a computer program) can perform the step of correlating the presence or absence of a polymorphism in an individual with an altered (e.g., increased or decreased) risk (or no altered risk) for CVD (particularly risk for CHD, such as MI, or hypertension) for the individual. Computer software can also perform the step of correlating the presence or absence of a polymorphism in an individual with the predicted response of the individual to a drug such as a statin. Accordingly, certain embodiments of the invention provide a computer (or other apparatus/device) programmed to carry out any of the methods described herein.
• Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits
• Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with CVD (particularly CHD, especially MI, or hypertension), including the transcript sequences (SEQ ID NOS:1-307), genomic sequences (SEQ ID NOS:1015-1400), and protein sequences (SEQ ID NOS:308-614) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5′) plus 100 nucleotides downstream (3′) of each SNP position (SEQ ID NOS:615-1014 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:1401-4006 and 5414 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc.
• Isolated Nucleic Acid Molecules
• The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1 and 2 may be interchangeably referred to throughout the present text as “SNP-containing nucleic acid molecules.” Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled “SNP Detection Reagents”), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.
• As used herein, an “isolated nucleic acid molecule” generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered “isolated.” Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered “isolated.” For example, recombinant DNA molecules contained in a vector are considered “isolated.” Further examples of “isolated” DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.
• Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.
• For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such instances the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.
• An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are referred to in Table 1 and provided in the Sequence Listing (SEQ ID NOS:1-307), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS:1015-1400). Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.
• Thus, the present invention also encompasses fragments of the nucleic acid sequences as disclosed in Tables 1 and 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414) and their complements. The actual sequences referred to in the tables are provided in the Sequence Listing. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides. Furthermore, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any other number in between). The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.
• An isolated nucleic acid molecule of the present invention further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H. A. Erlich, Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077 (1988)), strand displacement amplification (SDA) (U.S. Pat. Nos. 5,270,184 and 5,422,252), transcription-mediated amplification (TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat. No. 6,027,923) and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA) and self-sustained sequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874 (1990)). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5′ and 3′ to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.
• As used herein, an “amplified polynucleotide” of the invention is a SNP-containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.
• Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, 300, 400, or 500 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically up to about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600-700 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.
• In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1 and 2. Such a product may have additional sequences on its 5′ end or 3′ end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g., at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product. However, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product.
• The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.
• Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.
• The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences referred to in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.
• The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).
• The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.
• Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.
• Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675; 5,623,049; and 5,714,331. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule. Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art. See, e.g., Corey, “Peptide nucleic acids: expanding the scope of nucleic acid recognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup et al., “Peptide nucleic acids (PNA): synthesis, properties and potential applications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.
• The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters 4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal Chemistry Letters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272 (2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.
• Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP-containing nucleic acid molecules, SNP detection reagents (e.g., probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).
• The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1 and 2). Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.
• Further variants of the nucleic acid molecules disclosed in Tables 1 and 2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences referred to and shown in Tables 1 and 2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences referred to in Table 1.
• To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
• The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Computational Molecular Biology, A. M. Lesk, ed., Oxford University Press, N.Y (1988); Biocomputing: Informatics and Genome Projects, D. W. Smith, ed., Academic Press, N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin, eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology, G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence Analysis Primer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y. (1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (J Mol Biol (48):444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
• In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J. Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.
• The nucleotide and amino acid sequences of the present invention can further be used as a “query sequence” to perform a search against sequence databases; for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res 25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) and KERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December 2002)). For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.
• The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5′ untranslated regions (UTRs), 3′ untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents.
• SNP Detection Reagents
• In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (referred to in Table 1 as SEQ ID NOS:1-307), genomic sequences (referred to in Table 2 as SEQ ID NOS:1015-1400), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:1401-4006 and 5414), can be used for the design of SNP detection reagents. The actual sequences referred to in the tables are provided in the Sequence Listing. As used herein, a “SNP detection reagent” is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined). Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs referred to in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5′ and/or 3′ to a SNP position, particularly a region corresponding to the context sequences referred to in Table 1 and/or Table 2 (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414). Another example of a detection reagent is a primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.
• In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g., arrays or beads) or supplied in solution (e.g. probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.
• A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5′ and/or 3′ to the SNP position to carry out the desired assay.
• Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS:1-307), genomic sequences (SEQ ID NOS:1015-1400), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414) disclosed in the Sequence Listing and in Tables 1 and 2. The actual sequences referred to in the tables are provided in the Sequence Listing. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.
• In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm that starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.
• A primer or probe of the present invention is typically at least about 8 nucleotides in length. In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled “SNP Detection Kits and Systems”).
• For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as “allele-specific oligonucleotides,” “allele-specific probes,” or “allele-specific primers.” The design and use of allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection: A Practical Approach, Cotton et al., eds., Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.
• While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele-specific probe are as follows: prehybridization with a solution containing 5× standard saline phosphate EDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2× SSPE, and 0.1% SDS at 55° C. or room temperature.
• Moderate stringency hybridization conditions may be used for allele-specific primer extension reactions with a solution containing, e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may be carried out at an elevated temperature such as 60° C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about 100 mM KCl at a temperature of 46° C.
• In a hybridization-based assay, allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g., alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele. While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g., a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.
• In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5′ most end or the 3′ most end of the probe or primer. In a specific preferred embodiment that is particularly suitable for use in a oligonucleotide ligation assay (U.S. Pat. No. 4,988,617), the 3′most nucleotide of the probe aligns with the SNP position in the target sequence.
• Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are not limited to, the phosphotriester method described by Narang et al., Methods in Enzymology 68:90 (1979); the phosphodiester method described by Brown et al., Methods in Enzymology 68:109 (1979); the diethylphosphoamidate method described by Beaucage et al., Tetrahedron Letters 22:1859 (1981); and the solid support method described in U.S. Pat. No. 4,458,066.
• Allele-specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.
• In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448 (1989). Typically, the primer's 3′-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3′-most position of the oligonucleotide (i.e., the 3′-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below.
• In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3′-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3′-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3′-most position of the primer.
• In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.
• In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self-quenching probe such as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res 25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.
• The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.
• The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3′-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also contemplated by the present invention.
• SNP Detection Kits and Systems
• A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms “kits” and “systems,” as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g. TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip” systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.
• In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g. a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.
• SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.
• The terms “arrays,” “microarrays,” and “DNA chips” are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in Chee et al., U.S. Pat. No. 5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., Nat Biotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci 93:10614-10619 (1996), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.
• Nucleic acid arrays are reviewed in the following references: Zammatteo et al., “New chips for molecular biology and diagnostics,” Biotechnol Annu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications,” Psychiatr Genet 12(4):181-92 (December 2002); Heller, “DNA microarray technology: devices, systems, and applications,” Annu Rev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al., “Analysis of SNPs and other genomic variations using gel-based chips,” Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-density genechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol 77:21-42 (2002).
• Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.
• A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-30 nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5′ or 3′ sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g., specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.
• Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g., typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y. (1989).
• In other embodiments, the arrays are used in conjunction with chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection. U.S. patent applications that describe chemiluminescent approaches for microarray detection: Ser. Nos. 10/620,332 and 10/620,333. U.S. patents that describe methods and compositions of dioxetane for performing chemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024; 5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. And the U.S. published application that discloses methods and compositions for microarray controls: US2002/0110828.
• In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in-between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.
• A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application W095/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.
• Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.
• A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells), biopsies, buccal swabs or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparation system, and Roche Molecular Systems' COBAS AmpliPrep System.
• Another form of kit contemplated by the present invention is a compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser-induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art. See, e.g., Weigl et al., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev 55(3):349-77 (February 2003). In such microfluidic devices, the containers may be referred to as, for example, microfluidic “compartments,” “chambers,” or “channels.”
• Microfluidic devices, which may also be referred to as “lab-on-a-chip” systems, biomedical micro-electro-mechanical systems (bioMEMs), or multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro-machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Pat. No. 6,153,073, Dubrow et al., and U.S. Pat. No. 6,156,181, Parce et al.
• For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3′ end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.
• Uses of Nucleic Acid Molecules
• The nucleic acid molecules of the present invention have a variety of uses, especially for the diagnosis, prognosis, treatment, and prevention of CVD (particularly CHD, such as MI, or hypertension). For example, the nucleic acid molecules of the invention are useful for predicting an individual's risk for developing CVD (particularly the risk for CHD, especially MI, or hypertension), for prognosing the progression of CVD (e.g., the severity or consequences of CHD, particularly MI, or hypertension) in an individual, in evaluating the likelihood of an individual who has CVD (or who is at increased risk for CVD) of responding to treatment (or prevention) of CVD with a particular therapeutic agent, and/or predicting the likelihood that the individual will experience toxicity or other undesirable side effects from a treatment, etc. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.
• A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule referred to in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).
• A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).
• Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.
• Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphism(s) is at risk for developing CVD (or has already developed early stage CVD), or the likelihood that an individual will respond positively to a treatment (including preventive treatment) for CVD such as a particular therapeutic agent. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to the disease.
• Furthermore, the nucleic acid molecules of the invention are therefore useful for detecting a gene (gene information is disclosed in Table 2, for example) which contains a SNP disclosed herein and/or products of such genes, such as expressed mRNA transcript molecules (transcript information is disclosed in Table 1, for example), and are thus useful for detecting gene expression. The nucleic acid molecules can optionally be implemented in, for example, an array or kit format for use in detecting gene expression.
• The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.
• The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences referred to in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.
• The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g., an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.
• The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.
• The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP-containing nucleic acid molecule described herein.
• The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.
• The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allows, for example, effective clinical design of treatment compounds and dosage regimens.
• The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.
• The nucleic acid molecules of the invention are also useful in gene therapy in patients whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual.
• SNP Genotyping Methods
• The process of determining which nucleotide(s) is/are present at each of one or more SNP positions (such as a SNP position disclosed in Table 1 and/or Table 2), for either or both alleles, may be referred to by such phrases as SNP genotyping, determining the “identity” of a SNP, determining the “content” of a SNP, or determining which nucleotide(s)/allele(s) is/are present at a SNP position. Thus, these terms can refer to detecting a single allele (nucleotide) at a SNP position or can encompass detecting both alleles (nucleotides) at a SNP position (such as to determine the homozygous or heterozygous state of a SNP position). Furthermore, these terms may also refer to detecting an amino acid residue encoded by a SNP (such as alternative amino acid residues that are encoded by different codons created by alternative nucleotides at a SNP position).
• The present invention provides methods of SNP genotyping, such as for use in evaluating an individual's risk for developing CVD (particularly CHD, such as MI, or hypertension), for evaluating an individual's prognosis for disease severity and recovery, for predicting the likelihood that an individual who has previously had CVD (such as CHD, particularly MI, or hypertension) will have a recurrence of CVD again in the future, for implementing a preventive or treatment regimen for an individual based on that individual having an increased susceptibility for developing CVD (e.g., increased risk for CHD, particularly MI, or hypertension), in evaluating an individual's likelihood of responding to a therapeutic treatment (particularly for treating or preventing CVD), in selecting a treatment or preventive regimen (e.g., in deciding whether or not to administer a particular therapeutic agent to an individual having CVD, or who is at increased risk for developing CVD in the future), or in formulating or selecting a particular treatment or preventive regimen such as dosage and/or frequency of administration of a therapeutic agent or choosing which form/type of a therapeutic agent to be administered, such as a particular pharmaceutical composition or compound, etc.), determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, or selecting individuals for a clinical trial of a therapeutic agent (e.g., selecting individuals to participate in the trial who are most likely to respond positively to a therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to a therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular therapeutic agent based on their SNP genotype(s) to participate in a clinical trial of another therapeutic agent that may benefit them), etc.
• Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region (e.g., SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., “Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput,” Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of single nucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003); Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes,” Am J Pharmacogenomics 2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu Rev Genomics Hum Genet 2:235-58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, “High-throughput SNP analysis for genetic association studies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.
• Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al., Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); and Hayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and 51 protection or chemical cleavage methods.
• In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5′ most and the 3′ most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5′ or 3′ most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.
• During PCR, the 5′ nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.
• Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. It will be apparent to one of skill in the art that such primers and probes for detecting the SNPs of the present invention are useful in, for example, screening for individuals who are susceptible to developing CVD (particularly CHD, such as MI, or hypertension) and related pathologies, or in screening individuals who have CVD (or who are susceptible to CVD) for their likelihood of responding to a particular treatment (e.g., a particular therapeutic agent). These probes and primers can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).
• Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3′ most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3′ to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3′ most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP.
• The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA. The following U.S. patents describe OLA strategies for performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148; 5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array. U.S. application US01/17329 (and Ser. No. 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout. U.S. applications 60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.
• Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI-TOF (Matrix Assisted Laser Desorption Ionization—Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.
• Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5′) from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3′ end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5′ side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.
• The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al., “A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,” Rapid Commun Mass Spectrom 17(11):1195-202 (2003).
• The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, “SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry,” Bioinformatics 19 Suppl 1:144-153 (July 2003); Storm et al., “MALDI-TOF mass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62 (2003); Jurinke et al., “The use of Mass ARRAY technology for high throughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al., “Automated genotyping using the DNA MassArray technology,” Methods Mol Biol 187:179-92 (2002).
• SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized (e.g. Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv Chromatogr 36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol 38:147-159 (1993). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1 DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.
• Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). Myers et al., Nature 313:495 (1985). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products are related to base-sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence-dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel. PCR Technology: Principles and Applications for DNA Amplification Chapter 7, Erlich, ed., W. H. Freeman and Co, N.Y. (1992).
• Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis.
• SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.
• SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on an individual's genotype (“pharmacogenomics”), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent, predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent, and human identification applications such as forensics.
• Analysis of Genetic Associations Between SNPs and Phenotypic Traits
• SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (pharmacogenomics), drug toxicity screening, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest.
• Different study designs may be used for genetic association studies. Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disease is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disease in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disease, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disease are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.
• In both types of observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disease and the disease itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.
• In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with diseases and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.
• After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy-Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy-Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disease. B. Weir, Genetic Data Analysis, Sinauer (1990). To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3×2 table (3 genotypes×2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, −1, −1), additive or allelic (with contrast coefficients 1, 0, −1) and recessive (with contrast coefficients 1, 1, −2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.
• In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran-Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, getting a certain disease or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley (2000). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.
• In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together. Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disease-causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disease is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker-marker linkage disequilibrium measures, both D′ and r², are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Daly et al, Nature Genetics 29:232-235 (2001). Haplotype association with the disease status can be performed using such blocks once they have been elucidated.
• Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed that score tests can be done on haplotypes using the program “haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.
• An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the P value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted P value<0.2 (a significance level on the lenient side), for example, may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disease. It is preferred that a p-value<0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disease. It is more preferred that a p-value<0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wide error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate. Westfall et al., Multiple comparisons and multiple tests, SAS Institute (1999). Permutation tests to control for the false discovery rates, FDR, can be more powerful. Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57:1289-1300 (1995); Westfall and Young, Resampling-based Multiple Testing, Wiley (1993). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.
• In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then be performed by combining evidence of different studies. Modern Epidemiology 643-673, Lippincott, Williams & Wilkins (1998). If available, association results known in the art for the same SNPs can be included in the meta-analyses.
• Since both genotyping and disease status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disease classification error rates.
• It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies when prevalence of the disease is associated with different subpopulation groups. Ewens and Spielman, Am J Hum Genet 62:450-458 (1995). Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder can be used to adjust for the inflation of test statistics due to population stratification. Devlin et al., Biometrics 55:997-1004 (1999). The GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs. Devlin et al., Genet Epidem 21:273-284 (2001).
• While Pritchard's method recommended using 15-20 unlinked microsatellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000). Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).
• Once individual risk factors, genetic or non-genetic, have been found for the predisposition to disease, the next step is to set up a classification/prediction scheme to predict the category (for instance, disease or no-disease) that an individual will be in depending on his genotypes of associated SNPs and other non-genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks. Draper and Smith, Applied Regression Analysis, Wiley (1998). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods. The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002).
• Disease Diagnosis and Predisposition Screening
• Information on association/correlation between genotypes and disease-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disease for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with serious disease in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disease, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the risk allele(s).
• The SNPs of the invention may contribute to the development of CVD (e.g., CHD, such as MI, or hypertension), or to responsiveness of an individual to a therapeutic treatment, in different ways. Some polymorphisms occur within a protein coding sequence and contribute to disease phenotype by affecting protein structure. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.
• As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics” include, but are not limited to, any of the following: detection of CVD (such as CHD, e.g. MI, or hypertension) that an individual may presently have, predisposition/susceptibility/predictive screening (i.e., determining whether an individual has an increased or decreased risk of developing CVD in the future), prognosing the future course of CVD or recurrence of CVD in an individual, determining a particular type or subclass of CVD in an individual who currently or previously had CVD, confirming or reinforcing a previously made diagnosis of CVD, evaluating an individual's likelihood of responding positively to a particular treatment or therapeutic agent (particularly treatment or prevention of CVD), determining or selecting a therapeutic or preventive strategy that an individual is most likely to positively respond to (e.g., selecting a particular therapeutic agent or combination of therapeutic agents, or determining a dosing regimen, etc.), classifying (or confirming/reinforcing) an individual as a responder/non-responder (or determining a particular subtype of responder/non-responder) with respect to the individual's response to a drug treatment, and predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound. Such diagnostic uses can be based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.
• Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.
• Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g., alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in “linkage equilibrium.” In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.
• Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e., in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.
• For diagnostic purposes and similar uses, if a particular SNP site is found to be useful for, for example, predicting an individual's susceptibility to CVD or an individual's response to a treatment, then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for the same purposes. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g., CVD, or responder/non-responder to a drug treatment) that is influenced by the causative SNP(s). Therefore, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.
• Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the causative/associated SNP, other SNPs in the same intergenic region as the causative/associated SNP, SNPs that are outside but near a gene (e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) that harbors a causative/associated SNP, etc. Such useful LD SNPs can be selected from among the SNPs disclosed in Tables 1 and 2, for example.
• Linkage disequilibrium in the human genome is reviewed in Wall et al., “Haplotype blocks and linkage disequilibrium in the human genome,” Nat Rev Genet 4(8):587-97 (August 2003); Garner et al., “On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci,” Genet Epidemiol 24(1):57-67 (January 2003); Ardlie et al., “Patterns of linkage disequilibrium in the human genome,” Nat Rev Genet 3(4):299-309 (April 2002); erratum in Nat Rev Genet 3(7):566 (July 2002); and Remm et al., “High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (February 2002); J. B. S. Haldane, “The combination of linkage values, and the calculation of distances between the loci of linked factors,” J Genet 8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of the Natural History Society of Brünn) (1866); Genes IV, B. Lewin, ed., Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. Clark Principles of Population Genetics 2^nd ed., Sinauer Associates, Inc., Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide.2n^d ed., Johns Hopkins University Press (2004); R. C. Lewontin, “The interaction of selection and linkage. I. General considerations; heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction to Mathematical Statistics 2^nd ed., John Wiley & Sons, Inc., N.Y. (1954); R.R. Hudson, “Two-locus sampling distributions and their application,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M. Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EM algorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin, “Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet, S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm,” Ann Hum Genet 68(Pt 2):165-177 (2004); A. D. Long and C.H. Langley C H, “The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits,” Genome Research 9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley & Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methods for Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); The International HapMap Consortium, “The International HapMap Project,” Nature 426:789-796 (2003); The International HapMap Consortium, “A haplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A. Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The International HapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G. McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human genetic variation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005); J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies for common diseases and complex traits,” Nat Genet 6:95-108 (2005); S.J. Schrodi, “A probabilistic approach to large-scale association scans: a semi-Bayesian method to detect disease-predisposing alleles,” SAGMB 4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd, “Genome-wide association studies: theoretical and practical concerns,” Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkage disequilibrium in humans: models and data,” Am J Hum Genet 69:1-14 (2001).
• As discussed above, one aspect of the present invention is the discovery that SNPs that are in certain LD distance with an interrogated SNP can also be used as valid markers for determining whether an individual has an increased or decreased risk of having or developing CVD, for example. As used herein, the term “interrogated SNP” refers to SNPs that have been found to be associated with an increased or decreased risk of disease using genotyping results and analysis, or other appropriate experimental method as exemplified in the working examples described in this application. As used herein, the term “LD SNP” refers to a SNP that has been characterized as a SNP associating with an increased or decreased risk of diseases due to their being in LD with the “interrogated SNP” under the methods of calculation described in the application. Below, applicants describe the methods of calculation with which one of ordinary skilled in the art may determine if a particular SNP is in LD with an interrogated SNP. The parameter r² is commonly used in the genetics art to characterize the extent of linkage disequilibrium between markers (Hudson, 2001). As used herein, the term “in LD with” refers to a particular SNP that is measured at above the threshold of a parameter such as r² with an interrogated SNP.
• It is now common place to directly observe genetic variants in a sample of chromosomes obtained from a population. Suppose one has genotype data at two genetic markers located on the same chromosome, for the markers A and B . Further suppose that two alleles segregate at each of these two markers such that alleles A₁ and A₂ can be found at marker A and alleles B₁ and B₂ at marker B . Also assume that these two markers are on a human autosome. If one is to examine a specific individual and find that they are heterozygous at both markers, such that their two-marker genotype is A₁ A₂ B₁ B₂, then there are two possible configurations: the individual in question could have the alleles A₁ B₁ on one chromosome and A₂ B₂ on the remaining chromosome; alternatively, the individual could have alleles A₁ B₂ on one chromosome and A₂ B₁ on the other. The arrangement of alleles on a chromosome is called a haplotype. In this illustration, the individual could have haplotypes A₁B₁/A₂ B₂ or A₁ B₂/A₂B₁ (see Hartl and Clark (1989) for a more complete description). The concept of linkage equilibrium relates the frequency of haplotypes to the allele frequencies.
• Assume that a sample of individuals is selected from a larger population. Considering the two markers described above, each having two alleles, there are four possible haplotypes: A₁ B₁, A₁ B₂, A₂ B₁ and A₂ B₂. Denote the frequencies of these four haplotypes with the following notation.
• 
  P₁₁=freq(A₁ B₁)   (1)
• 
  P₁₂=freq(A₁ B₂)   (2)
• 
  P₂₁=freq(A₂ B₁)   (3)
• 
  P₂₂=freq(A₂ B₂)   (4)
• The allele frequencies at the two markers are then the sum of different haplotype frequencies, it is straightforward to write down a similar set of equations relating single-marker allele frequencies to two-marker haplotype frequencies:
• 
  p ₁=freq(A ₁)=P ₁₁ +P ₁₂   (5)
• 
  p ₂=freq(A ₂)=P ₂₁ +P ₂₂   (6)
• 
  q ₁=freq(B ₁)=P ₁₁ +P ₂₁   (7)
• 
  q ₂=freq(B ₂)=P ₁₂ +P ₂₂   (8)
• Note that the four haplotype frequencies and the allele frequencies at each marker must sum to a frequency of 1.
• 
  P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1   (9)
• 
  p ₁ +p ₂=1   (10)
• 
  q ₁ +q ₂=1   (11)
• If there is no correlation between the alleles at the two markers, one would expect that the frequency of the haplotypes would be approximately the product of the composite alleles. Therefore,
• 
  P₁₁≈p₁ q₁   (12)
• 
  P₁₂≈p₁ q₂   (13)
• 
  P₂₁≈p₂ q₁   (14)
• 
  P₂₂≈p₂ q₂   (15)
• These approximating equations (12)-(15) represent the concept of linkage equilibrium where there is independent assortment between the two markers—the alleles at the two markers occur together at random. These are represented as approximations because linkage equilibrium and linkage disequilibrium are concepts typically thought of as properties of a sample of chromosomes; and as such they are susceptible to stochastic fluctuations due to the sampling process. Empirically, many pairs of genetic markers will be in linkage equilibrium, but certainly not all pairs.
• Having established the concept of linkage equilibrium above, applicants can now describe the concept of linkage disequilibrium (LD), which is the deviation from linkage equilibrium. Since the frequency of the A₁ B₁ haplotype is approximately the product of the allele frequencies for A₁ and B₁ under the assumption of linkage equilibrium as stated mathematically in (12), a simple measure for the amount of departure from linkage equilibrium is the difference in these two quantities, D,
• 
  D=P ₁₁ −p _q q ₁   (16)
• D=0 indicates perfect linkage equilibrium. Substantial departures from D=0 indicates LD in the sample of chromosomes examined. Many properties of D are discussed in Lewontin (1964) including the maximum and minimum values that D can take. Mathematically, using basic algebra, it can be shown that D can also be written solely in terms of haplotypes:
• 
  D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁   (17)
• If one transforms D by squaring it and subsequently dividing by the product of the allele frequencies of A₁, A₂, B₁ and B₂, the resulting quantity, called r², is equivalent to the square of the Pearson's correlation coefficient commonly used in statistics (e.g. Hoel, 1954).
• $\begin{array}{cc}{r}^2=\frac{D^2}{p_1{p}_2{q}_1{q}_2}& \left(18\right)\end{array}$
• As with D , values of r² close to 0 indicate linkage equilibrium between the two markers examined in the sample set. As values of r² increase, the two markers are said to be in linkage disequilibrium. The range of values that r² can take are from 0 to 1. r²=1 when there is a perfect correlation between the alleles at the two markers.
• In addition, the quantities discussed above are sample-specific. And as such, it is necessary to formulate notation specific to the samples studied. In the approach discussed here, three types of samples are of primary interest: (i) a sample of chromosomes from individuals affected by a disease-related phenotype (cases), (ii) a sample of chromosomes obtained from individuals not affected by the disease-related phenotype (controls), and (iii) a standard sample set used for the construction of haplotypes and calculation pairwise linkage disequilibrium. For the allele frequencies used in the development of the method described below, an additional subscript will be added to denote either the case or control sample sets.
• 
  p_1,cs=freq(A₁ in cases)   (19)
• 
  p_2,cs=freq(A₂ in cases)   (20)
• 
  q_1,cs=freq(B₁ in cases)   (21)
• 
  q_2,cs=freq(B₂ in cases)   (22)
Similarly,
• 
  p_1,ct=freq(A₁ in controls)   (23)
• 
  p_2,ct=freq(A₂ in controls)   (24)
• 
  q_1,ct=freq(B₁ in controls)   (25)
• 
  q_2,ct=freq(B₂ in controls)   (26)
• As a well-accepted sample set is necessary for robust linkage disequilibrium calculations, data obtained from the International HapMap project (The International HapMap Consortium 2003, 2005; Thoris son et al, 2005; McVean et al, 2005) can be used for the calculation of pairwise r² values. Indeed, the samples genotyped for the International HapMap Project were selected to be representative examples from various human sub-populations with sufficient numbers of chromosomes examined to draw meaningful and robust conclusions from the patterns of genetic variation observed. The International HapMap project website (hapmap.org) contains a description of the project, methods utilized and samples examined. It is useful to examine empirical data to get a sense of the patterns present in such data.
• Haplotype frequencies were explicit arguments in equation (18) above. However, knowing the 2-marker haplotype frequencies requires that phase to be determined for doubly heterozygous samples. When phase is unknown in the data examined, various algorithms can be used to infer phase from the genotype data. This issue was discussed earlier where the doubly heterozygous individual with a 2-SNP genotype of A₁ A₂ B₁ B₂ could have one of two different sets of chromosomes: A₁ B₁/A₂ B₂ or A₁ B₂/A₂ B₁. One such algorithm to estimate haplotype frequencies is the expectation-maximization (EM) algorithm first formalized by Dempster et al. (1977). This algorithm is often used in genetics to infer haplotype frequencies from genotype data (e.g. Excoffier and Slatkin (1995); Tregouet et al. (2004)). It should be noted that for the two-SNP case explored here, EM algorithms have very little error provided that the allele frequencies and sample sizes are not too small. The impact on r² values is typically negligible.
• As correlated genetic markers share information, interrogation of SNP markers in LD with a disease-associated SNP marker can also have sufficient power to detect disease association (Long and Langley (1999)). The relationship between the power to directly find disease-associated alleles and the power to indirectly detect disease-association was investigated by Pritchard and Przeworski (2001). In a straight-forward derivation, it can be shown that the power to detect disease association indirectly at a marker locus in linkage disequilibrium with a disease-association locus is approximately the same as the power to detect disease-association directly at the disease-association locus if the sample size is increased by a factor of
• $\frac{1}{r^2}$
• (the reciprocal of equation 18) at the marker in comparison with the disease-association locus.
• Therefore, if one calculated the power to detect disease-association indirectly with an experiment having N samples, then equivalent power to directly detect disease-association (at the actual disease-susceptibility locus) would necessitate an experiment using approximately r²N samples. This elementary relationship between power, sample size and linkage disequilibrium can be used to derive an r² threshold value useful in determining whether or not genotyping markers in linkage disequilibrium with a SNP marker directly associated with disease status has enough power to indirectly detect disease-association.
• To commence a derivation of the power to detect disease-associated markers through an indirect process, define the effective chromosomal sample size as
• $\begin{array}{cc}n=\frac{4N_{cs}{N}_{ct}}{N_{cs}+N_{ct}};& \left(27\right)\end{array}$
• where N_cs and N_ct are the numbers of diploid cases and controls, respectively. This is necessary to handle situations where the numbers of cases and controls are not equivalent. For equal case and control sample sizes, N_cs=N_ct=N , the value of the effective number of chromosomes is simply n=2N—as expected. Let power be calculated for a significance level α (such that traditional P-values below α will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(·). Mathematically,
• $\begin{array}{cc}\Phi \left(x\right)=\frac{1}{\sqrt{2\pi }}\underset{-\infty }{\overset{x}{\int }}{e}^{-\frac{{\theta }^2}{2}}d\theta & \left(28\right)\end{array}$
• Alternatively, the following error function notation (Erf) may also be used,
• $\begin{array}{cc}\Phi \left(x\right)=\frac{1}{2}\left[1+\mathrm{Erf}\left(\frac{x}{\sqrt{2}}\right)\right]& \left(29\right)\end{array}$
• For example, Φ(1.644854)=0.95. The value of r² may be derived to yield a pre-specified minimum amount of power to detect disease association though indirect interrogation. Noting that the LD SNP marker could be the one that is carrying the disease- association allele, therefore that this approach constitutes a lower-bound model where all indirect power results are expected to be at least as large as those interrogated.
• Denote by β the error rate for not detecting truly disease-associated markers. Therefore, 1−β is the classical definition of statistical power. Substituting the Pritchard-Pzreworski result into the sample size, the power to detect disease association at a significance level of α is given by the approximation
• $\begin{array}{cc}1-\beta \cong \Phi \left[\frac{❘q_{1,\mathrm{cs}}-q_{1,\mathrm{ct}}❘}{\sqrt{\frac{q_{1,\mathrm{cs}}\left(1-q_{1,\mathrm{cs}}\right)+q_{1,\mathrm{ct}}\left(1-q_{1,\mathrm{ct}}\right)}{r^{2}n}}}-Z_{1-\alpha /2}\right];& \left(30\right)\end{array}$
• where Z_u is the inverse of the standard normal cumulative distribution evaluated at u (u ∈ (0,1)). Z_u=Φ⁻¹ (u), where Φ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore 1−α/2=0.975, one obtains Z_0.975=1.95996. Next, setting power equal to a threshold of a minimum power of T,
• $\begin{array}{cc}T=\Phi \left[\frac{❘q_{1,\mathrm{cs}}-q_{1,\mathrm{ct}}❘}{\sqrt{\frac{q_{1,\mathrm{cs}}\left(1-q_{1,\mathrm{cs}}\right)+q_{1,\mathrm{ct}}\left(1-q_{1,\mathrm{ct}}\right)}{r^{2}n}}}-Z_{1-\alpha /2}\right]& \left(31\right)\end{array}$
• and solving for r², the following threshold r² is obtained:
• $\begin{array}{cc}{r}_T^2={\frac{\lfloor q_{1,\mathrm{cs}}\left(1-q_{1,\mathrm{cs}}\right)+q_{1,\mathrm{ct}}\left(1-q_{1,\mathrm{ct}}\right)\rfloor }{{n\left(q_{1,\mathrm{cs}}-q_{1,\mathrm{ct}}\right)}^2}\left[{\Phi }^{-1}\left(T\right)+Z_{1-\alpha /2}\right]}^2& \left(32\right)\end{array}$
Or,
• $\begin{array}{cc}{r}_T^2=\frac{{\left(Z_T+Z_{1-\alpha /2}\right)}^2}{n}\left[\frac{{{q_{1,\mathrm{cs}}-{(}_{q_{1,\mathrm{cs}}})}^2+q_{1,\mathrm{ct}}-{(}_{q_{1,\mathrm{ct}}})}^2}{{{(}_{q_{1,\mathrm{cs}}-q_{1,\mathrm{ct}}})}^2}\right]& \left(33\right)\end{array}$
• Suppose that r² is calculated between an interrogated SNP and a number of other SNPs with varying levels of LD with the interrogated SNP. The threshold value r_T ² is the minimum value of linkage disequilibrium between the interrogated SNP and the potential LD SNPs such that the LD SNP still retains a power greater or equal to T for detecting disease-association. For example, suppose that SNP rs200 is genotyped in a case-control disease-association study and it is found to be associated with a disease phenotype. Further suppose that the minor allele frequency in 1,000 case chromosomes was found to be 16% in contrast with a minor allele frequency of 10% in 1,000 control chromosomes. Given those measurements one could have predicted, prior to the experiment, that the power to detect disease association at a significance level of 0.05 was quite high—approximately 98% using a test of allelic association. Applying equation (32) one can calculate a minimum value of r² to indirectly assess disease association assuming that the minor allele at SNP rs200 is truly disease-predisposing for a threshold level of power. If one sets the threshold level of power to be 80%, then r_T ²=0.489 given the same significance level and chromosome numbers as above. Hence, any SNP with a pairwise r² value with rs200 greater than 0.489 is expected to have greater than 80% power to detect the disease association. Further, this is assuming the conservative model where the LD SNP is disease-associated only through linkage disequilibrium with the interrogated SNP rs200.
• The contribution or association of particular SNPs and/or SNP haplotypes with disease phenotypes, such as CVD, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as CVD, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with CVD might indicate a probability of 20% that an individual has or is at risk of developing CVD, whereas detection of five SNPs, each of which correlates with CVD, might indicate a probability of 80% that an individual has or is at risk of developing CVD. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of CVD, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors.
• It will be understood by practitioners skilled in the treatment or diagnosis of CVD that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) of developing CVD, and/or pathologies related to CVD, but rather to indicate a certain increased (or decreased) degree or likelihood of developing the disease based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments or to allow an individual carrying one or more significant SNPs or SNP haplotypes to foresee warning signs such as minor clinical symptoms, or to have regularly scheduled physical exams to monitor for appearance of a condition in order to identify and begin treatment of the condition at an early stage. Particularly with diseases that are extremely debilitating or fatal if not treated on time, the knowledge of a potential predisposition, even if this predisposition is not absolute, would likely contribute in a very significant manner to treatment efficacy.
• The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids. The trait analyzed using the diagnostics of the invention may be any detectable trait that is commonly observed in pathologies and disorders related to CVD.
• Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele.
• In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the “gene response” of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.
• Therapeutics, Pharmacogenomics, and Drug Development
• Therapeutic Methods and Compositions
• In certain aspects of the invention, there are provided methods of assaying (i.e., testing) one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a therapeutic or preventive agent to the individual based on the allele(s) present at the SNP(s) having indicated that the individual can benefit from the therapeutic or preventive agent.
• In further aspects of the invention, there are provided methods of assaying one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a diagnostic agent (e.g., an imaging agent), or otherwise carrying out further diagnostic procedures on the individual, based on the allele(s) present at the SNP(s) having indicated that the diagnostic agents or diagnostics procedures are justified in the individual.
• In yet other aspects of the invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g., a small molecule drug, antibody, peptide, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to an individual who has been tested for one or more SNPs provided by the present invention.
• Pharmacogenomics
• The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent or pharmaceutical compound, or to a class of such compounds. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001); Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); and Linder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.
• The discovery of SNPs in drug metabolizing enzymes, drug transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.
• As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disease susceptibility gene.
• Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in predicting an individual's predisposition to CVD (e.g., CHD, such as MI, or hypertension) and in predicting an individual's responsiveness to a drug (particularly for treating or preventing CVD). Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et al., Trends in Biotechnology, August . 2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.
• Pharmacogenomics in general is discussed further in Rose et al., “Pharmacogenetic analysis of clinically relevant genetic polymorphisms,” Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med 34(5):357-79 (2002); Maimone et al., “Pharmacogenomics of neurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February 2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (December 1999). Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., “Pharmacogenomics of drugs affecting the cardiovascular system,” Clin Chem Lab Med 41(4):590-9 (April 2003); Mukherjee et al., “Pharmacogenomics in cardiovascular diseases,” Prog Cardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et al., “Cardiovascular pharmacogenetics in the SNP era,” J Thromb Haemost 1(7):1398-402 (July 2003). Pharmacogenomics as it relates to cancer is discussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, and the individual patient,” Cancer Invest 21(4):630-40 (2003); and Watters et al., “Cancer pharmacogenomics: current and future applications,” Biochim Biophys Acta 1603(2):99-111 (March 2003).
• Clinical Trials
• In certain aspects of the invention, there are provided methods of using the SNPs disclosed herein to identify or stratify patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent.
• For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype, such as selecting individuals for inclusion in a clinical trial and/or assigning individuals to a particular group within a clinical trial (e.g., an “arm” or “cohort” of the trial). For example, individuals with SNP genotypes that indicate that they are likely to positively respond to a drug can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or who are at risk for suffering toxic effects or other adverse reactions, can be excluded from the clinical trials. This not only can improve the safety of clinical trials, but also can enhance the chances that the trial will demonstrate statistically significant efficacy.
• Thus, certain embodiments of the invention provide methods for conducting a clinical trial of a therapeutic agent in which a human is selected for inclusion in the clinical trial and/or assigned to a particular group within a clinical trial based on the presence or absence of one or more SNPs disclosed herein. In certain embodiments, the therapeutic agent is a statin.
• In certain exemplary embodiments, SNPs of the invention can be used to select individuals who are unlikely to respond positively to a particular therapeutic agent (or class of therapeutic agents) based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them. Thus, in certain embodiments, the SNPs of the invention can be used to identify patient populations who do not adequately respond to current treatments and are therefore in need of new therapies. This not only benefits the patients themselves, but also benefits organizations such as pharmaceutical companies by enabling the identification of populations that represent markets for new drugs, and enables the efficacy of these new drugs to be tested during clinical trials directly in individuals within these markets.
• The SNP-containing nucleic acid molecules of the present invention are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of a variant gene, or encoded product, particularly in a treatment regimen or in clinical trials. Thus, the gene expression pattern can serve as an indicator for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance, as well as an indicator for toxicities. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant.
• Furthermore, the SNPs of the present invention may have utility in determining why certain previously developed drugs performed poorly in clinical trials and may help identify a subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby “rescuing” previously developed drugs, and enabling the drug to be made available to a particular CVD patient population that can benefit from it.
• Identification, Screening, and Use of Therapeutic Agents
• The SNPs of the present invention also can be used to identify novel therapeutic targets for CVD. For example, genes containing the disease-associated variants (“variant genes”) or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disease or prevent or delay disease onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.
• The invention further provides methods for identifying a compound or agent that can be used to treat CVD. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell-free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.
• Variant gene expression in a CVD patient can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).
• Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g., mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.
• Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as CVD that is characterized by variant gene expression (e.g., either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.
• The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e., suppression or antagonization) of nucleic acid expression.
• Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.
• Pharmaceutical Compositions and Administration Thereof
• Any of the CVD-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating or preventing CVD or related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.
• In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
• Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70-kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.
• In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
• The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
• Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
• Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
• Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences 18^th ed., E.W. Martin, ed., Mack Publishing Company (1990).
• The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80% wt.
• Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of a CVD-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different CVD-associated protein to thereby counteract the effects of CVD.
• For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.
• Nucleic Acid-Based Therapeutic Agents
• The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology: Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). An antisense nucleic acid molecule is generally designed to be complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g., RNaseH or RNase L) that cleave the target RNA. Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates. See, e.g., Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g., in gene knock-out or knock-down experiments).
• Antisense technology is further reviewed in: Lavery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al., “Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther 5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvement through novel chemical modifications,” Eur J Biochem 270(8):1628-44 (April 2003); Dias et al., “Antisense oligonucleotides: basic concepts and mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen, “Clinical development of antisense oligonucleotides as anti-cancer therapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisense anticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets 1(3):177-96 (November 2001); and Bennett, “Efficiency of antisense oligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev 12(3):215-24 (June 2002).
• The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g., SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g., a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g., an alternative SNP nucleotide that encodes a protein having normal function).
• Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as CVD, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.
• The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21, 22, or 23 nucleotides in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917 (2002). Accordingly, an aspect of the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21, 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi. Because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g., for turning off defective, disease-causing genes), and are also useful for characterizing and validating gene function (e.g., in gene knock-out or knock-down experiments).
• The following references provide a further review of RNAi: Reynolds et al., “Rational siRNA design for RNA interference,” Nat Biotechnol 22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewide view of gene silencing by small interfering RNAs,” PNAS 100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” J Biol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms and their potential use for therapy,” Curr Opin Chem Biol 6(6):829-34 (December 2002); Lavery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” Trends Genet 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing in therapeutic intervention,” Drug Discovery Today 7(20):1040-1046 (October 2002); McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia et al., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June 1999).
• Other Therapeutic Aspects
• SNPs have many important uses in drug discovery, screening, and development, and thus the SNPs of the present invention are useful for improving many different aspects of the drug development process.
• For example, a high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population. Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and development process. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).
• Knowledge of variants (e.g., SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g., a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants. Rothberg, Nat Biotechnol 19(3):209-11 (March 2001). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.
• Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).
• Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1 and 2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.
• Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1, thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1 and 2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.
• A subject suffering from a pathological condition ascribed to a SNP, such as CVD, may be treated so as to correct the genetic defect. See Kren et al., Proc Natl Acad Sci USA 96:10349-10354 (1999). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild-type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.
• In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.
• Human Identification Applications
• In addition to their diagnostic, therapeutic, and preventive uses in CVD and related pathologies, the SNPs provided by the present invention are also useful as human identification markers for such applications as forensics, paternity testing, and biometrics. See, e.g., Gill, “An assessment of the utility of single nucleotide polymorphisms (SNPs) for forensic purposes,” Int J Legal Med 114(4-5):204-10 (2001). Genetic variations in the nucleic acid sequences between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Determination of which nucleotides occupy a set of SNP positions in an individual identifies a set of SNP markers that distinguishes the individual. The more SNP positions that are analyzed, the lower the probability that the set of SNPs in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked (i.e., inherited independently). Thus, preferred sets of SNPs can be selected from among the SNPs disclosed herein, which may include SNPs on different chromosomes, SNPs on different chromosome arms, and/or SNPs that are dispersed over substantial distances along the same chromosome arm.
• Furthermore, among the SNPs disclosed herein, preferred SNPs for use in certain forensic/human identification applications include SNPs located at degenerate codon positions (i.e., the third position in certain codons which can be one of two or more alternative nucleotides and still encode the same amino acid), since these SNPs do not affect the encoded protein. SNPs that do not affect the encoded protein are expected to be under less selective pressure and are therefore expected to be more polymorphic in a population, which is typically an advantage for forensic/human identification applications. However, for certain forensics/human identification applications, such as predicting phenotypic characteristics (e.g., inferring ancestry or inferring one or more physical characteristics of an individual) from a DNA sample, it may be desirable to utilize SNPs that affect the encoded protein.
• For many of the SNPs disclosed in Tables 1 and 2 (which are identified as “Applera” SNP source), Tables 1 and 2 provide SNP allele frequencies obtained by re-sequencing the DNA of chromosomes from 39 individuals (Tables 1 and 2 also provide allele frequency information for “Celera” source SNPs and, where available, public SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies provided in Tables 1 and 2 enable these SNPs to be readily used for human identification applications. Although any SNP disclosed in Table 1 and/or Table 2 could be used for human identification, the closer that the frequency of the minor allele at a particular SNP site is to 50%, the greater the ability of that SNP to discriminate between different individuals in a population since it becomes increasingly likely that two randomly selected individuals would have different alleles at that SNP site. Using the SNP allele frequencies provided in Tables 1 and 2, one of ordinary skill in the art could readily select a subset of SNPs for which the frequency of the minor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables 1 and 2 provide allele frequencies based on the re-sequencing of the chromosomes from 39 individuals, a subset of SNPs could readily be selected for human identification in which the total allele count of the minor allele at a particular SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other number in-between.
• Furthermore, Tables 1 and 2 also provide population group (interchangeably referred to herein as ethnic or racial groups) information coupled with the extensive allele frequency information. For example, the group of 39 individuals whose DNA was re-sequenced was made-up of 20 Caucasians and 19 African-Americans. This population group information enables further refinement of SNP selection for human identification. For example, preferred SNPs for human identification can be selected from Tables 1 and 2 that have similar allele frequencies in both the Caucasian and African-American populations; thus, for example, SNPs can be selected that have equally high discriminatory power in both populations. Alternatively, SNPs can be selected for which there is a statistically significant difference in allele frequencies between the Caucasian and African-American populations (as an extreme example, a particular allele may be observed only in either the Caucasian or the African-American population group but not observed in the other population group); such SNPs are useful, for example, for predicting the race/ethnicity of an unknown perpetrator from a biological sample such as a hair or blood stain recovered at a crime scene. For a discussion of using SNPs to predict ancestry from a DNA sample, including statistical methods, see Frudakis et al., “A Classifier for the SNP-Based Inference of Ancestry,” Journal of Forensic Sciences 48(4):771-782 (2003).
• SNPs have numerous advantages over other types of polymorphic markers, such as short tandem repeats (STRs). For example, SNPs can be easily scored and are amenable to automation, making SNPs the markers of choice for large-scale forensic databases. SNPs are found in much greater abundance throughout the genome than repeat polymorphisms. Population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. SNPs are mutationally more stable than repeat polymorphisms. SNPs are not susceptible to artifacts such as stutter bands that can hinder analysis. Stutter bands are frequently encountered when analyzing repeat polymorphisms, and are particularly troublesome when analyzing samples such as crime scene samples that may contain mixtures of DNA from multiple sources. Another significant advantage of SNP markers over STR markers is the much shorter length of nucleic acid needed to score a SNP. For example, STR markers are generally several hundred base pairs in length. A SNP, on the other hand, comprises a single nucleotide, and generally a short conserved region on either side of the SNP position for primer and/or probe binding. This makes SNPs more amenable to typing in highly degraded or aged biological samples that are frequently encountered in forensic casework in which DNA may be fragmented into short pieces.
• SNPs also are not subject to microvariant and “off-ladder” alleles frequently encountered when analyzing STR loci. Microvariants are deletions or insertions within a repeat unit that change the size of the amplified DNA product so that the amplified product does not migrate at the same rate as reference alleles with normal sized repeat units. When separated by size, such as by electrophoresis on a polyacrylamide gel, microvariants do not align with a reference allelic ladder of standard sized repeat units, but rather migrate between the reference alleles. The reference allelic ladder is used for precise sizing of alleles for allele classification; therefore alleles that do not align with the reference allelic ladder lead to substantial analysis problems. Furthermore, when analyzing multi-allelic repeat polymorphisms, occasionally an allele is found that consists of more or less repeat units than has been previously seen in the population, or more or less repeat alleles than are included in a reference allelic ladder. These alleles will migrate outside the size range of known alleles in a reference allelic ladder, and therefore are referred to as “off-ladder” alleles. In extreme cases, the allele may contain so few or so many repeats that it migrates well out of the range of the reference allelic ladder. In this situation, the allele may not even be observed, or, with multiplex analysis, it may migrate within or close to the size range for another locus, further confounding analysis.
• SNP analysis avoids the problems of microvariants and off-ladder alleles encountered in STR analysis. Importantly, microvariants and off-ladder alleles may provide significant problems, and may be completely missed, when using analysis methods such as oligonucleotide hybridization arrays, which utilize oligonucleotide probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed, may lead to improper statistical analysis, since their frequencies in the population are generally unknown or poorly characterized, and therefore the statistical significance of a matching genotype may be questionable. All these advantages of SNP analysis are considerable in light of the consequences of most DNA identification cases, which may lead to life imprisonment for an individual, or re-association of remains to the family of a deceased individual.
• DNA can be isolated from biological samples such as blood, bone, hair, saliva, or semen, and compared with the DNA from a reference source at particular SNP positions. Multiple SNP markers can be assayed simultaneously in order to increase the power of discrimination and the statistical significance of a matching genotype. For example, oligonucleotide arrays can be used to genotype a large number of SNPs simultaneously. The SNPs provided by the present invention can be assayed in combination with other polymorphic genetic markers, such as other SNPs known in the art or STRs, in order to identify an individual or to associate an individual with a particular biological sample.
• Furthermore, the SNPs provided by the present invention can be genotyped for inclusion in a database of DNA genotypes, for example, a criminal DNA databank such as the FBI's Combined DNA Index System (CODIS) database. A genotype obtained from a biological sample of unknown source can then be queried against the database to find a matching genotype, with the SNPs of the present invention providing nucleotide positions at which to compare the known and unknown DNA sequences for identity. Accordingly, the present invention provides a database comprising novel SNPs or SNP alleles of the present invention (e.g., the database can comprise information indicating which alleles are possessed by individual members of a population at one or more novel SNP sites of the present invention), such as for use in forensics, biometrics, or other human identification applications. Such a database typically comprises a computer-based system in which the SNPs or SNP alleles of the present invention are recorded on a computer readable medium.
• The SNPs of the present invention can also be assayed for use in paternity testing. The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in the putative father and the child, with the SNPs of the present invention providing nucleotide positions at which to compare the putative father's and child's DNA sequences for identity. If the set of polymorphisms in the child attributable to the father does not match the set of polymorphisms of the putative father, it can be concluded, barring experimental error, that the putative father is not the father of the child. If the set of polymorphisms in the child attributable to the father match the set of polymorphisms of the putative father, a statistical calculation can be performed to determine the probability of coincidental match, and a conclusion drawn as to the likelihood that the putative father is the true biological father of the child.
• In addition to paternity testing, SNPs are also useful for other types of kinship testing, such as for verifying familial relationships for immigration purposes, or for cases in which an individual alleges to be related to a deceased individual in order to claim an inheritance from the deceased individual, etc. For further information regarding the utility of SNPs for paternity testing and other types of kinship testing, including methods for statistical analysis, see Krawczak, “Informativity assessment for biallelic single nucleotide polymorphisms,” Electrophoresis 20(8):1676-81 (June 1999).
• The use of the SNPs of the present invention for human identification further extends to various authentication systems, commonly referred to as biometric systems, which typically convert physical characteristics of humans (or other organisms) into digital data. Biometric systems include various technological devices that measure such unique anatomical or physiological characteristics as finger, thumb, or palm prints; hand geometry; vein patterning on the back of the hand; blood vessel patterning of the retina and color and texture of the iris; facial characteristics; voice patterns; signature and typing dynamics; and DNA. Such physiological measurements can be used to verify identity and, for example, restrict or allow access based on the identification. Examples of applications for biometrics include physical area security, computer and network security, aircraft passenger check-in and boarding, financial transactions, medical records access, government benefit distribution, voting, law enforcement, passports, visas and immigration, prisons, various military applications, and for restricting access to expensive or dangerous items, such as automobiles or guns. See, for example, O'Connor, Stanford Technology Law Review, and U.S. Pat. No. 6,119,096.
• Groups of SNPs, particularly the SNPs provided by the present invention, can be typed to uniquely identify an individual for biometric applications such as those described above. Such SNP typing can readily be accomplished using, for example, DNA chips/arrays. Preferably, a minimally invasive means for obtaining a DNA sample is utilized. For example, PCR amplification enables sufficient quantities of DNA for analysis to be obtained from buccal swabs or fingerprints, which contain DNA-containing skin cells and oils that are naturally transferred during contact.
• Further information regarding techniques for using SNPs in forensic/human identification applications can be found, for example, in Current Protocols in Human Genetics 14.1-14.7, John Wiley & Sons, N.Y. (2002).
• Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof
• Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules
• The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art-known (i.e., wild-type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are referred to as SEQ ID NOS:308-614 in Table 1 and provided in the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic proteins/peptides/polypeptides of the present invention. The terms “protein,” “peptide,” and “polypeptide” are used herein interchangeably.
• A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains.
• As used herein, a protein or peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.
• As used herein, “substantially free of cellular material” includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.
• The language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.
• An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).
• The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons that contain a SNP of the present invention.
• Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.
• The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.
• The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.
• The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein. “Operatively linked” indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence. See Ausubel et al., Current Protocols in Molecular Biology (1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.
• In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells (e g , mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, “Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems,” Appl Microbiol Biotechnol 60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al., “Designing proteins that work using recombinant technologies,” Curr Pharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al., “Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16 (October 1997).
• In certain embodiments, novel compositions of the present invention also relate to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., allelic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry.
• Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, an aspect of the present invention that is specifically contemplated are polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1, but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.
• Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.
• Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.
• Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found, for example, in Bowie et al., Science 247:1306-1310 (1990).
• Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.
• Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis, particularly using the amino acid sequence and polymorphism information provided in Table 1. Cunningham et al., Science 244:1081-1085 (1989). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling. Smith et al., J Mol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).
• Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.
• Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
• Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Particularly common modifications, for example glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, are described in most basic texts, such as Proteins—Structure and Molecular Properties 2nd Ed., T. E. Creighton, W. H. Freeman and Company, N.Y. (1993); F. Wold, Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson, ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol 182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).
• The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g., substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.
• As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g., a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g., act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g., active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis). Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002).
• Uses of Variant Proteins
• The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art. See, e.g., Molecular Cloning: A Laboratory Manual, Sambrook and Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology: Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel, eds., Academic Press (1987).
• In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS:308-614. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non-synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other.
• In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing CVD or for determining predisposition to CVD in a human, for treating and/or preventing CVD, or for predicting an individual's response to a treatment (particularly treatment or prevention of CVD), etc. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as “protein chips”). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications.
• One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.
• In vitro methods for detection of the variant proteins associated with CVD that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15; 71(12):294R-304R (June 1999).
• Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing.
• Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
• Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g., small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.
• As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g., small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.
• The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).
• The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.
• A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non-variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.
• Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.
• Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′)₂, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).
• One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.
• The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.
• Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.
• The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein. Hodgson, Bio/technology, 10(9), 973-80 (Sept. 1992).
• To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be bound to a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., ³⁵S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.
• Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.
• Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as CVD. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.
• The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.
• In yet another aspect of the invention, variant proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. See, e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J Biol Chem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924 (1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO 94/10300. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein-mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.
• The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein.
• Antibodies Directed to Variant Proteins
• The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non-variant proteins, i.e., the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).
• As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad Sci USA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), a humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544 (1989)), a bispecific antibody with two binding specificities (Segal et al., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7 (2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., J Immunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer or trimer), and a minibody.
• Many methods are known in the art for generating and/or identifying antibodies to a given target antigen. Harlow, Antibodies,
• Cold Spring Harbor Press, N.Y. (1989). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g., a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.
• Monoclonal antibodies can be produced by hybridoma technology, which immortalizes cells secreting a specific monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975). The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000); Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding. U.S. Pat. No. 5,637,677.
• Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read-through mutation caused by a SNP). Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-10 contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.
• Detection of an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.
• Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,” Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancer antibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg, “Advancing role of radiolabeled antibodies in the therapy of cancer,” Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et al., “Antibody-based therapeutics in oncology,” Expert Rev Anticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecific antibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97 (February 2003); von Mehren et al., “Monoclonal antibody therapy for cancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson et al., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekke et al., “Therapeutic antibodies for human diseases at the dawn of the twenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003); Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos et al., “Monoclonal antibodies in immune and inflammatory diseases,” Curr Opin Biotechnol 13(6):615-20 (December 2002); Kellermann et al., “Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics,” Curr Opin Biotechnol 13(6):593-7 (December 2002); Pini et al., “Phage display and colony filter screening for high-throughput selection of antibody libraries,” Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra et al., “Pharmacokinetics and biodistribution of genetically engineered antibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); and Tangri et al., “Rationally engineered proteins or antibodies with absent or reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).
• Uses of Antibodies
• Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disease progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as in CVD, or during treatment. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.
• Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.
• Further, antibodies can be used to assess expression of the variant protein in disease states such as in active stages of the disease or in an individual with a predisposition to a disease related to the protein's function, such as CVD, or during the course of a treatment regime. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to diagnose CVD or to predict an individual's response to a treatment or predisposition/susceptibility to CVD, as indicated by the presence of the variant protein.
• Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.
• Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.
• Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.
• The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol. Leong et al., Cytokine 16:106 (2001).
• The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.
• Vectors and Host Cells
• The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.
• A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.
• The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).
• Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.
• The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.
• In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.
• In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. See, e.g., Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).
• A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).
• The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g., tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.
• A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the
• The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, Escherichia coli, Streptomyces spp., and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila spp., animal cells such as COS and CHO cells, and plant cells.
• As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).
• Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (S. Gottesman, Gene Expression Technology: Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).
• The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari et al., EMBO J 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).
• The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).
• In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (B. Seed, Nature 329:840(1987)) and pMT2PC (Kaufman et al., EMBO J 6:187-195 (1987)).
• The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).
• The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.
• The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y. (2000).
• Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.
• In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.
• Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.
• While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.
• Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.
• Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.
• It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.
• For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.
• Uses of Vectors and Host Cells, and Transgenic Animals
• Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production.
• Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.
• Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal's milk and then recovered.
• A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.
• Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.
• Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No. 4,873,191 by Wagner et al., and in B. Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.
• In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.
• Clones of the non-human transgenic animals described herein can also be produced according to the methods described, for example, in I. Wilmut et al., Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G_o phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g., a somatic cell) is isolated.
• Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).
• For further information regarding transgenic animals, see Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Petters et al., “Transgenic animals as models for human disease,” Transgenic Res 9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenic animals in understanding molecular mechanisms of toxicity,” J Pharm Pharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant protein production in transgenic animals,” Curr Opin Biotechnol 7(5):536-40 (October 1996); Houdebine, “Transgenic animal bioreactors,” Transgenic Res 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creating transgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl et al., “Artificial chromosome vectors and expression of complex proteins in transgenic animals,” Theriogenology 59(1):107-13 (January 2003).
EXAMPLES
• The following examples are offered to illustrate, but not limit, the claimed invention.
Example 1: SNP rs197922 in GOSR2 is Associated with Hypertension
• Overview
• A missense SNP in GOSR2 (Lys67Arg, rs197922) was analyzed for association with hypertension and blood pressure. Logistic and linear regression was used to test the association of the GOSR2 SNP with hypertension and blood pressure among 3,528 blacks and 9,861 whites from the Atherosclerosis Risk in Communities (ARIC) study. Race-specific regression models of hypertension were adjusted for age and gender. Adjustments were made for anti-hypertensive medication use when testing the association with blood pressure.
• The Lys67 allele of GOSR2 was associated with increased hypertension risk in whites (adjusted odds ratio=1.09, P=0.01) (in blacks, adjusted odds ratio=0.96, P=0.47). The Lys67 allele was also associated with systolic blood pressure (SBP) in both races (adjusted β=0.87, P<0.001 and adjusted (β=1.05, P=0.05 for whites and blacks, respectively). This allele was also associated with SBP in white participants of the Women's Health Study (P=0.11).
• See Meyer et al., Am J Hypertens. 2009 February; 22(2):163-8, incorporated herein by reference in its entirety.
• Methods
• Atherosclerosis Risk in Communities Study (ARIC)
• Study Population
• The Atherosclerosis Risk in Communities (ARIC) study is a longitudinal cohort study of atherosclerosis, cardiovascular disease, and their risk factors. The population and study methods have been described in detail elsewhere.¹² Briefly, from 1987 to 1989, 15,792 participants between the ages of 45 to 64 were sampled from four study sites in the United States: Forsyth County, North Carolina; Jackson, Miss.; suburban Minneapolis, Minn.; and Washington County, Maryland. At baseline and in three-year intervals following the baseline visit (1990-1992, 1993-1995, and 1996-1998) participants were interviewed and underwent a brief clinical examination. The study was approved by institutional review boards from each field center and written informed consent was obtained from participants before each examination. Follow-up examinations were supplemented with annual telephone interviews.
• In the current analysis, individuals from races other than white or black (n=48) or blacks from Minnesota and Washington County (n=55) were excluded due to small numbers. Those who refused to participate in genetic studies (n=44) were also excluded. Since incident CHD was the outcome used in the primary study in which GOSR2 was selected, and since results for hypertension were similar with or without exclusion for prevalent CHD, participants were excluded for prevalent CHD (n=762), missing CHD (337), or prevalent stroke (n=331), leaving 14,215 participants (10,401 whites, 3,814 blacks, 6,146 males and 8,069 females). During 196,069 person-years of follow-up (mean 13.8 years), 1,747 (12%) of the 14,215 ARIC participants in this analysis had an incident CHD event. For the present analysis of GOSR2 and hypertension, those missing information for GOSR2 genotype (n=826) were further excluded, resulting in 13,389 participants (9,861 whites, 3,528 blacks, 5,787 males and 7,602 females). At baseline, 4,416 of the 13,389 participants (33%) reported prevalent hypertension.
• Measurements
• Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured after resting for 5 minutes in the seated position using a random-zero sphygmomanometer. Second and third readings were averaged to derive the blood pressure measures used here. Hypertension was defined as a SBP of 140 mmHg or greater, a DBP of 90 mmHg or greater, or use of blood pressure lowering medications in the past two weeks. Waist circumference was measured once at the umbilicus with an anthropometric tape. Levels of fasting triglycerides,¹³ total cholesterol,¹⁴ high density lipoprotein cholesterol (HDL),¹⁵ and glucose¹⁶ were measured in blood samples using standard methods that have been reported previously. Low density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula.¹⁷ Carotid artery (CA) intima media thickness (IMT) was measured using high-resolution B-mode ultrasound following structured protocols as described elsewhere.^{18, 19} The mean of measurements taken at six carotid artery sites were used. High IMT was defined as ≥75% tile separately for men and women. Diabetes was defined as a fasting blood glucose of 126 mg/dL or more, a non-fasting blood glucose of 200 mg/dL or more, self-reported diabetes, or use of diabetes medications in the past two weeks. Incident CHD was defined by documented MI, unstable angina, sudden coronary death, or non-elective cardiovascular surgical procedures. Incident CHD events were determined through 2003. Follow-up time for CHD events was calculated from the date of the baseline visit to the date of the first CHD event for CHD cases or until either Dec. 31, 2003 or the last date of contact for those who did not have a CHD event. Genotypes in the ARIC participants were determined by an oligonucleotide ligation procedure that combined PCR amplification of target sequences from 3 ng of genomic DNA with subsequent allele-specific oligonucleotide ligation.²⁰ The ligation products of the two alleles were separated by hybridization to product specific oligonucleotides, each coupled to spectrally distinct Luminex100 xMAP microspheres (Luminex, Austin, Tex.). The captured products were fluorescently labeled with streptavidin R-phycoerythrin (Prozyme, San Leandro, Calif.), sorted on the basis of microsphere spectrum, and detected by a Luminex100 instrument.
• SNP Selection
• SNPs were identified that were associated with CHD in two antecedent case control studies of MI. Briefly, 20,009 SNPs (in 9,874 Entrez or Ensembl genes) were tested in one case control study (475 cases of MI and 649 non-MI controls). The 1,548 SNPs that were associated with MI in this first study (P<0.1), were then tested in a second case-control study of MI (793 MI cases and 1,000 healthy controls). Further details of the antecedent case control studies can be found in other references.^21-23 77 SNPs were found that were associated with MI (P<0.1) and had the same risk alleles in both studies (Table 7). The risk alleles of 72 of these 77 SNPs were then tested for their association with time to incident CHD in ARIC using Cox proportional hazards models, where the SNPs were modeled in an additive manner along with gender and age (five of the 77 SNPs were not tested in ARIC because good quality multiplex assays could not be made for them). One of the SNPs that was associated with CHD was in GOSR2 (Lys67Arg, rs197922). Complete results for the association tests between incident CHD in ARIC for 34 of the 72 SNPs are reported in Morrison et al.²³ and Bare et al.²²
• Statistics
• Means and standard deviations or frequencies and percents were calculated for continuous and categorical variables, respectively. Triglyceride levels were natural-log transformed for comparison of mean levels by genotype. Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated excluding participants who were using anti-hypertensive medications. Differences in means or frequencies by genotype were determined using the F-test or chi-square test as appropriate for continuous and categorical variables. In all regression models, the GOSR2 SNP was coded in an additive manner. Linear regression was used to analyze the association between the GOSR2 SNP and the continuous variables, such as SBP and DBP. Logistic regression was used to analyze the association between the GOSR2 SNP and prevalent hypertension, elevated SBP, DBP, and IMT (≥75% tile). Linear and logistic regression models were adjusted for age and gender. Regression models of SBP and DBP were additionally adjusted for use of anti-hypertensive medications. Since additive models have been shown to perform well even when the underlying inheritance model is recessive or dominant,^{24, 25} and since there is no previous literature indicating an inheritance model for the GOSR2 SNP and hypertension, estimates for the additive model for GOSR2 were reported. Differences in results by gender were evaluated using the likelihood ratio test. No significant differences by gender were detected, so gender-specific results are not presented. Power to detect an association between the GOSR2 SNP and hypertension with OR of 1.1 was 79% among white participants of ARIC and 45% among black participants.
• Results
• GOSR2 genotype frequencies differed by race (P<0.001; whites: ArgArg 43.2%, LysArg 44.6%, LysLys 12.2%; blacks: ArgArg 48.1%, LysArg 42.4%, LysLys 9.5%) but were consistent with Hardy-Weinberg expectations for both whites (Pearson chisquare=1.57; P=0.21) and blacks (Pearson chisquare=0.08; P=0.78).
• Means and percentages for the demographic and clinical variables at baseline are presented in Table 8 according to race and genotype. Mean SBP (P=0.004) and DBP (P=0.09) among those not using anti-hypertensive medications, waist circumference (P=0.05), and CA IMT (P=0.02) differed by genotype among whites (there were no differences among blacks). The GOSR2 SNP was significantly associated with SBP in both whites (β=0.87, P<0.001) and blacks (β=1.05, P=0.05) after adjustment for age, gender, and use of anti-hypertensive medications. The GOSR2 SNP was also associated with DBP among whites after adjustment (β=0.37, P=0.01) (in blacks, after adjustment, (β=0.44, P=0.14). Prevalent hypertension at baseline also differed by genotype among whites (P<0.01) (among blacks, P=0.66).
• The risk associated with the GOSR2 SNP and blood pressure was assessed using dichotomized SBP and DBP variables (>75% tile). An association was found between the Lys67 allele of the GOSR2 SNP and elevated SBP (OR: 1.08; 95% CI: 1.00 to 1.15) and elevated DBP (OR: 1.08; 95% CI: 1.01 to 1.16) among whites (Table 9). The risk associated with GOSR2 and a dichotomized IMT variable was also assessed and found to be associated with elevated CA IMT (OR: 1.09; 95% CI: 1.01 to 1.17) among whites. The effect sizes were similar across measures of high blood pressure and consistent with the comparison of means by genotype in Table 8. In a genotypic assessment of the GOSR2 variant associated with hypertension among whites, the OR for LysArg compared to ArgArg and LysLys compared to ArgArg were similar in magnitude (OR: 1.18; 95% CI: 1.06 to 1.30 and OR: 1.13; 95% CI: 0.97 to 1.31, respectively), consistent with a dominant inheritance model for GOSR2 and hypertension in whites.
• Discussion
• The GOSR2 Lys67Arg SNP (rs197922) was analyzed for association with hypertension in the ARIC study and it was found that the Lys67 allele was associated with hypertension, as well as with elevated SBP and DBP. The Lys67 allele had been shown to be associated with increased risk of CHD in antecedent studies (Table 7). In this example, the GOSR2 Lys67 allele was found to be associated with increased occurrence of hypertension in white participants in the ARIC study (additive OR: 1.09; 95% CI: 1.02 to 1.17; dominance OR: 1.16; 95% CI 1.06 to 1.28). This Lys67 allele was also found to be associated with quantitative traits such as SBP, DBP, and CA IMT among whites in ARIC. Linear regression revealed that the Lys67 allele was also associated with SBP among black participants of ARIC after adjusting for age, gender, and use of anti-hypertensive medication.
• The association between the Lys67 allele of GOSR2 and blood pressure was also tested in white participants of the Women's Health Study (WHS).²⁶ Allele frequencies of Lys67Arg in the white participants of WHS were similar to those of white participants of ARIC (data not shown). An association with increased SBP was observed for the Lys67 allele of GOSR2 in this WHS population (OR=1.03; P=0.04, in an ordinal logistic regression of nine SBP categories after adjusting for age) (OR=1.03 and P=0.11 after additionally adjusting for use of anti-hypertensive medications).
• GOSR2
• GOSR2 codes for a vesicular N-ethylmaleimide sensitive factor attachment protein receptor (v-SNARE) that is involved in intra-Golgi trafficking of vesicles.²⁹ v-SNAREs such as GOSR2 interact with target-localized SNAREs (t-SNAREs) to allow directed movement of macromolecules, such as insulin, leptin, and angiotensinogen, between Golgi compartments.^30-32 GOSR2 is expressed in multiple tissues.⁷
• GOSR2 is located under linkage peaks with hypertension on human chromosome 17,^8-10 as well as the syntenic rat chromosome 10, and murine chromosome 11.¹¹ Despite the evidence in both humans and animal models for the region's contribution to blood pressure and risk of hypertension, an association between GOSR2 and hypertension has not previously been reported. Other genes in this region may be considered candidates for essential hypertension, but of these only MYL4 (myosin light polypeptide 4) is in a LD region with the GOSR2 rs197922 polymorphism. Using data from the International HapMap Project,²⁸ one SNP (rs16941671) from MYL4 was in moderate LD with GOSR2 rs197922 (r²=0.19; D′=0.87) in the CEPH (Utah residents with ancestry from northern and western Europe) population.
• Since GOSR2 codes for a vesicular membrane protein involved in intra-Golgi protein trafficking, the results described here indicate that protein processing in the Golgi influences blood pressure levels and risk of hypertension, and altered regulation of protein trafficking (such as may be attributable to a SNP such as rs197922 that can cause alternative amino acids to be encoded) within the Golgi may contribute to blood pressure and essential hypertension.
• References (Reference Numbers Corresponds to Example 1 Only, With the Exception of Reference Numbers 33 and 34 Which Correspond to Table 7)
• 1. Kearney P M, Whelton M, Reynolds K, Muntner P, Whelton P K, He J. Global burden of hypertension: Analysis of worldwide data. Lancet. 2005; 365:217-223.
• 2. Centers for Disease Control and Prevention. National Center for Health Statistics. FastStats.
• 3. Ostchega Y, Yoon S S, Hughes J, Louis T. Hypertension awareness, treatment and control—continued disparities in adults: United states, 2005-2006. 2008; NCHS data brief no 3. Hyatsville, Md.: National Center for Health Statistics.
• 4. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA. 2003; 290:199-206.
• 5. Cowley A W, Jr. The genetic dissection of essential hypertension. Nature Reviews Genetics. 2006; 7:829-840.
• 6. Binder A. A review of the genetics of essential hypertension. Curr Opin Cardiol. 2007; 22:176-184.
• 7. Lowe S L, Peter F, Subramaniam V N, Wong S H, Hong W. A SNARE involved in protein transport through the Golgi apparatus. Nature. 1997; 389:881-884.
• 8. Levy D, DeStefano A L, Larson M G, O'Donnell, C J, Lifton R P, Gavras H, Cupples L A, Myers R H. Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham heart study. Hypertension. 2000; 36:477-483.
• 9. Baima J, Nicolaou M, Schwartz F, DeStefano A L, Manolis A, Gavras I, Laffer C, Elijovich F, Farrer L, Baldwin C T, Gavras H. Evidence for linkage between essential hypertension and a putative locus on human chromosome 17. Hypertension. 1999; 34:4-7.
• 10. Julier C, Delepine M, Keavney B, Terwilliger J, Davis S, Weeks D E, Bui T, Jeunemaitre X, Velho G, Froguel P, Ratcliffe P, Corvol P, Soubrier F, Lathrop G M. Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. Hum Mol Genet. 1997; 6:2077-2085.
• 11. Knight J, Munroe P B, Pembroke J C, Caulfield M J. Human chromosome 17 in essential hypertension. Ann Hum Genet. 2003; 67:193-206.
• 12. The Atherosclerosis Risk in Communities (ARIC) study: Design and objectives. The ARIC investigators. Am J Epidemiol. 1989; 129:687-702.
• 13. Nagele U, Hagele E O, Sauer G, Wiedemann E, Lehmann P, Wahlefeld A W, Gruber W. Reagent for the enzymatic determination of serum total triglycerides with improved lipolytic efficiency. Journal of Clinical Chemistry & Clinical Biochemistry. 1984; 22:165-174.
• 14. Siedel J, Hagele E O, Ziegenhorn J, Wahlefeld A W. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem. 1983; 29:1075-1080.
• 15. Warnick G R, Benderson J, Albers J J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982; 28:1379-1388.
• 16. Operations manual no. 10: Clinical chemistry determinations, version 1.0.; Chapel Hill: ARIC Coordinating Center, School of Public Health, University of North Carolina. 1987.
• 17. Friedewald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499-502.
• 18. Anonymous. High-resolution B-mode ultrasound scanning methods in the Atherosclerosis Risk in Communities study (ARIC). The ARIC study group. Journal of Neuroimaging. 1991; 1:68-73.
• 19. Stevens J, Tyroler H A, Cai J, Paton C C, Folsom A R, Tell G S, Schreiner P J, Chambless L E. Body weight change and carotid artery wall thickness. The Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 1998; 147:563-573.
• 20. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z, Arellano A R, Lumley T, Rice K, lakoubova O, Luke M M, Young B A, Malloy M J, Kane J P, Ellis S G, Tracy R P, Devlin J J, Psaty B M. Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2008:28:173-179.
• 21. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M, lakoubova O A, Pullinger C R, Cassano J, Aouizerat B E, Fenwick R G, Reitz R E, Catanese J J, Leong D U, Zellner C, Sninsky J J, Topol E J, Devlin J J, Kane J P. Identification of four gene variants associated with myocardial infarction. Am J Hum Genet. 2005; 77:596-605.
• 22. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M, lakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S, Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants identify elevated genetic risk for coronary heart disease. Genetics in Medicine. 2007; 9:682-689.
• 23. Morrison A C, Bare L A, Chambless L E, Ellis S G, Malloy M, Kane J P, Pankow J S, Devlin J J, Willerson J T, Boerwinkle E. Prediction of coronary heart disease risk using a genetic risk score: The Atherosclerosis Risk in Communities study. Am J Epiderniol. 2007; 166:28-35.
• 24. Horvath S, Xu X, Laird N M. The family based association test method: Strategies for studying general genotype-phenotype associations. European Journal of Human Genetics. 2001; 9:301-306.
• 25. Balding D J. A tutorial on statistical methods for population association studies. Nature Reviews Genetics. 2006; 7:781-791.
• 26. Rexrode K M, Lee I M, Cook N R, Hennekens C H, Buring J E. Baseline characteristics of participants in the Women's Health Study. Journal of Womens Health & Gender-Based Medicine. 2000; 9:19-27.
• 27. Bui T D, Levy E R, Subramaniam V N, Lowe S L, Hong W. cDNA characterization and chromosomal mapping of human golgi SNARE GS27 and GS28 to chromosome 17. Genomics. 1999; 57:285-288.
• 28. The International HapMap Consortium. The International HapMap Project. Nature. 2003; 426:789-796.
• 29. Hay J C, Klumperman J, Oorschot V, Steegmaier M, Kuo C S, Scheller R H. Localization, dynamics, and protein interactions reveal distinct roles for ER and golgi SNAREs. J Cell Biol. 1998; 141:1489-1502.
• 30. Sollner T, Bennett M K, Whiteheart S W, Scheller R H, Rothman J E. A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell. 1993; 75:409-418.
• 31. Sollner T, Whiteheart S W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman J E. SNAP receptors implicated in vesicle targeting and fusion. Nature. 1993; 362:318-324.
• 32. Rothman J E. Mechanisms of intracellular protein transport. Nature. 1994; 372:55-63.
• 33. Morrison A C, Bare L A, Chambless L E, Ellis S G, Malloy M, Kane J P, Pankow J S, Devlin J J, Willerson J T, Boerwinkle E. Prediction of coronary heart disease risk using a genetic risk score: The Atherosclerosis Risk in Communities study. Am J Epidemiol. 2007; 166:28-35.
• 34. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M, Iakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S, Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants identify elevated genetic risk for coronary heart disease. Genetics in Medicine. 2007; 9:682-689.
Example 2: Identification of Five SNPs in Four Genes that are Associated with Myocardial Infarction
• Overview
• 17,576 SNPs that could affect gene function or expression were analyzed for association with MI. The testing of these SNPs was staged in three case—control studies of MI. In the first study (762 cases, 857 controls), 17,576 SNPs were tested and 1,949 SNPs were found that were associated with MI (P<0.05). These 1,949 SNPs were tested in a second study (579 cases and 1159 controls) and it was found that 24 of these SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, these 24 SNPs were tested in a third study (475 cases and 619 controls) and it was found that 5 of these SNPs, which are located in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA), were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies.
• Thus, 5 SNPs were identified that are associated with MI.
• See Shiffman et al., PLoS ONE. 2008 Aug. 6; 3(8):e2895, incorporated herein by reference in its entirety.
• Methods
• Objectives
• To identify genetic polymorphisms associated with MI, three case-control studies comprising cases with a history of MI and controls without a history of MI were interrogated. The first two case-control studies (Study 1 and Study 2) identified SNPs associated with MI. The hypotheses that these SNPs are associated with MI were tested in Study 3. The allele frequency of each SNP was determined in pools of case and control DNA prior to determining the genotype of a smaller number of SNPs for all individual DNA samples.
• Participants
• Participants in Study 1 and Study 2 were enrolled between July 1989 and May 2005 by the University of California, San Francisco (UCSF) Genomic Resource in Arteriosclerosis. UCSF samples received at the Celera genotyping facility by May 2004 were considered for inclusion in Study 1. Samples that arrived past that date were considered for Study 2. Cases in Study 1 and
• Study 2 included patients who had undergone diagnostic or interventional cardiac catheterization and patients of the UCSF Lipid Clinic. Controls were enrolled by the UCSF Genomic Resource in Arteriosclerosis and included UCSF staff, patients of UCSF Clinics, and senior citizens who participated in physical activities at regional community centers and events for senior citizens. A history of MI for Study 1 cases was verified by a clinical chart review or by The International Classification of Diseases, 9^th Revision (ICD9) codes 410 or 411 in the patient records. MI status for Study 2 cases was determined by ICD9 codes 410 or 411 or by a self-reported history of MI. To characterize the accuracy of these self—reported histories, medical record review for a sample of Study 2 cases resulted in verification of the self-reported MI status for 98% of the sample (verification by electrocardiogram, cardiac enzymes or imaging). Controls had no history of MI, diabetes or symptomatic vascular disease. All participants of Study 1 and Study 2 chose Caucasian as their ethnicity in response to a multiple-choice questionnaire.
• Participants in Study 3 were patients of the Cleveland Clinic Foundation (CCF) Heart Center who had undergone diagnostic or interventional cardiac catheterization between July 2001 and March 2003 and enrolled in the Genebank at Cleveland Clinic Study. A history of MI was verified by electrocardiogram, cardiac enzymes, or perfusion imaging. Controls had less than 50% coronary luminal narrowing. All participants in Study-3 selected North European, Eastern European, or ‘other Caucasian’ as the description of both their mother and father on the enrollment questionnaire. The demographic and risk factor characteristics of the participants in the 3 studies are presented in Table 11.
• SNP Selection
• The 17,576 SNPs investigated in Study 1 are located in 10,152 genes. These SNPs could potentially affect gene function or expression. Most (65%) of these SNPs were missense, nonsense, or were located in acceptor and donor splice sites. Other SNPs were located in transcription factor binding sites, microRNA binding sites, exon splice enhancer and silencer sites, or in untranslated regions of mRNA.
• Allele Frequency and Genotype Determination
• DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes) fluorescent dye. DNA pools, typically of 50 cases or controls, were made by mixing equal volumes of standardized DNA from each individual member of the pool. Each allele was amplified separately by PCR using 3 ng of pooled DNA. The allele frequency was calculated from amplification curves for each allele. At least four independent pools of DNA were amplified in duplicate for each allele. Genotyping of individual DNA samples was similarly performed using 0.3 ng of DNA.
• Ethics
• Subjects of all three studies gave informed consent and completed an Institutional Review Board approved questionnaire.
• Statistical Methods
• Association between MI status and allele frequencies was assessed by two-tailed χ² tests, and between MI status and genotype by logistic regression using an additive inheritance model (Wald test). In Study 2 and Study 3, since a single prespecified risk allele was tested for each SNP, one-sided P values and 90% confidence intervals are presented (for odds ratios greater than one, there is 95% confidence that the true risk estimate is greater than the lower bound of a 90% confidence interval). A P threshold value of 0.05 was used in all three studies, and adjusted for multiple testing by calculating the false discovery rate (FDR) in Study 3. FDR was calculated using the MULTTEST procedure (SAS statistical package Version 9.1); for SNPs that were in the same gene, only the SNP with the higher (less significant) P value was included in the calculation.
• Results
• The allele frequencies of 17,576 putative functional SNPs were measured in Study 1 cases and controls using pooled DNA samples, and 1,949 SNPs were identified that were associated with MI (P<0.05) and had minor allele frequency estimates that were greater than 1%. For these 1,949 SNPs, allele frequencies in Study 2 cases and controls were determined using pooled DNA samples and it was verified that the risk allele identified in Study 1 was also associated with risk of MI in Study 2. For those SNPs that were associated with MI and had the same risk alleles in both pooling studies, the association of the SNP with MI in Study 1 and Study 2 was then confirmed by genotyping individual DNA samples. It was found that the risk alleles of 24 SNPs in 23 genes were associated with MI in both studies using an additive inheritance model (Table 12) and a P value threshold of 0.05. Next, the hypotheses that the risk alleles of these 24 SNPs would be associated with MI were tested in Study 3. It was found that the risk allele of 5 SNPs, in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI using an additive inheritance model after adjustment for age and sex (Table 13) (false discovery rate=0.23). The distribution of the genotypes for each of the SNPs did not deviate from what was expected under Hardy-Weinberg equilibrium (P>0.5). Further adjustment for traditional risk factors (dyslipidemia, hypertension, smoking status, and BMI), did not appreciably change the risk estimate for the four SNPs LPA, FXN (2 SNPs), and HLA-DPB2 (Table 13; for the ENO1 SNP, after further adjustment for traditional risk factors, OR=1.09, 90% CI 0.85-1.38, P=0.28, and the ENO1 SNP trended toward association with dyslipidemia (P=0.1)).
• Discussion
• An analysis was conducted of 17,576 SNPs that could potentially affect gene function or expression in three case-control studies of MI, and 5 SNPs were identified in four genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) that were associated with MI.
• The first SNP is located in ENO1, a gene that encodes α-enolase, a glycolytic enzyme that catalyzes the conversion of 2-phospho-D-glycerate to phosphoenolpyruvate. α-enolase is also known to be a plasminogen receptor on the surface of hematopoietic cells and endothelial cells [11]. Thus, a-enolase could contribute to fibrinolysis, hemostasis, and arterial thrombus formation—processes that are critical in the pathophysiology of MI. The SNP in ENO1 (rs1325920) is located about 1 kb upstream of the gene and could be involved in transcriptional regulation.
• Two of the SNPs are in the FXN gene. The FXN gene encodes Frataxin, a mitochondrial protein involved in maintaining cellular iron homeostasis [12]. Expanded GAA triplet repeats in intron 1 of FXN leads to silencing of the FXN gene and to accumulation of iron in the mitochondria, which makes mitochondria sensitive to oxidative stress [13]. These changes lead to Friedreich's ataxia, an autosomal recessive disease of the central nervous system that is frequently associated hypertrophic cardiomyopathy [12]. The two SNPs in FXN found to be associated with MI are located in the 3′ untranslated region of FXN (rs10890) and in a putative transcription factor binding site (rs3793456), thus one or both of these SNPs could have an effect on FXN gene expression. These two SNPs are in linkage disequilibrium (r²=0.57 in Study 1).
• The fourth SNP (rs3798220 in LPA) encodes a methionine to isoleucine substitution at amino acid 4399 of apolipoprotein(a). It has been previously shown that this SNP is associated with coronary artery narrowing and with increased levels of plasma lipoprotein(a) in case-control studies [10]. This SNP was also associated with incident myocardial infarction in the Cardiovascular Health
• Study, a population-based prospective study of about 5000 individuals aged 65 or older [14].
• As described above, certain aspects of the invention relate to using SNP rs3798220 for utilities related to hormone replacement therapy (HRT).
• The fifth SNP that is associated with MI in this study is in HLA-DPB2 (rs35410698). HLA-DPB2 is a pseudogene in the Human Leukocyte Antigen (HLA) region [15].
• References (Reference Numbers Correspond to Example 2 Only)
• 1. American Heart Association (2002) Heart disease and stroke statistics: 2005 update. American Heart Association, Dallas
• 2. Marenberg M E, Risch N, Berkman L F, Floderus B, de Faire U (1994) Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 330:1041-1046
• 3. Cohen J C, Boerwinkle E, Mosley T H Jr, Hobbs H H (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264-1272.
• 4. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt N P et al. (2008) Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358:1240-1249.
• 5. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R et al. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488-1491.
• 6. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T et al. (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491-1493.
• 7. Shiffman D, Rowland C M, Sninsky J J, Devlin J J (2006) Polymorphisms associated with coronary heart disease: better by the score. Curr Opin Mol Ther 8:493-499.
• 8. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M et al. (2005) Identification of four gene variants associated with myocardial infarction. Am J Hum Genet 77:596-605.
• 9. Shiffman D, Rowland C M, Louie J Z, Luke M M, Bare L A et al. (2006) Gene Variants of VAMP8 and HNRPUL1 Are Associated With Early-Onset Myocardial Infarction. Arterioscler Thromb Vasc Biol 26:1613-1618.
• 10. Luke M M, Kane J P, Liu D M, Rowland C M, Shiffman D et al. (2007) A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler Thromb Vasc Biol 27:2030-2036.
• 11. Pancholi V. (2001) Multifunctional alpha-enolase: its role in diseases. Cell Mol Life Sci 58:902-920.
• 12. Gottesfeld J M (2007) Small molecules affecting transcription in Friedreich ataxia. Pharmacol Ther 116:236-248.
• 13. Al-Mandawi S, Pinto R M, Varshney D, Lawrence L, Lowrie M B et al. (2006) Genomics 88:580-590.
• 14. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z et al. (2008) Association of Gene Variants With Incident Myocardial Infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 28:173-179.
• 15. de Bakker P I, McVean G, Sabeti P C, Miretti M M, Green T et al. (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38:1166-1172.
• 16. Topol E J, McCarthy J, Gabriel S, Moliterno D J, Rogers W J et al. (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 104:2641-2644.
Example 3: Fine-Mapping SNPs Associated with CVD
• SNPs Surrounding GOSR2 SNP rs197922 (hCV2275273)
• As described above in Example 1, a SNP in GOSR2 (rs197922, hCV2275273) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 17 surrounding this GOSR2 SNP, other SNPs in a 215 kb region surrounding rs197922 were genotyped and analyzed. This region of 215 kb included all the SNPs with r²>0.3 with rs197922 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF Study 1 (“UCSF1”) (793 MI cases and 1000 controls). For SNPs that were in LD with rs197922 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 10.
• SNPs Surrounding ENO1 SNP rs1325920 (hCV8824241)
• As described above in Example 2, a SNP in ENO1 (rs1325920, hCV8824241) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 1 surrounding this ENO1 SNP, other SNPs in a 582 kb region surrounding rs1325920 were genotyped and analyzed. This region of 582 kb included all the SNPs with r²>0.3 with rs1325920 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs1325920 (r²>0.3), tagging SNPs with r²>0.90 were used. Some of the SNPs that were associated with MI in UCSF1 were also genotyped in a second sample set, UCSF2 (579 MI cases and 1159 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 and were also associated with MI in UCSF2 (or were not tested in UCSF2) are provided in Table 14.
• SNPs Surrounding FXN SNP rs10890 (hCV1463226)
• As described above in Example 2, a SNP in FXN (rs10890, hCV1463226) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 9 surrounding this FXN SNP, other SNPs in a 203 kb region surrounding rs10890 were genotyped and analyzed. This region of 203 kb included all the SNPs with r²>0.3 with rs10890 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs10890 (r²>0.3), tagging SNPs with r²>0.90 were used. Some of the SNPs that were associated with MI in UCSF1 were also genotyped in a second sample set, UCSF2 (579 MI cases and 1159 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 and were also associated with MI in UCSF2 (or were not tested in UCSF2) are provided in Table 15.
• SNPs Surrounding RERE SNP rs10779705 (hCV32055477)
• As shown in Table 14 (SNPs surrounding ENO1), a SNP in RERE (rs10779705, hCV32055477) was been identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 1 surrounding this RERE SNP, other SNPs in a 596 kb region surrounding rs10779705 were genotyped and analyzed. This region of 596 kb included all the SNPs with r²>0.3 with rs10779705 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs10779705 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 16.
• SNPs Surrounding VAMP8 SNP rs1010 (hCV2091644)
• A SNP in VAMP8 (rs1010, hCV2091644) has been identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 2 surrounding this VAMP8 SNP, other SNPs in a 220 kb region surrounding rs1010 were genotyped and analyzed. This region of 220 kb included all the SNPs with r²>0.3 with rs1010 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (793 MI cases and 1000 controls). For SNPs that were in LD with rs1010 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 17.
• SNPs Surrounding LPA SNP rs3798220 (hCV25930271)
• As described above in Example 2, a SNP in LPA (rs3798220, hCV25930271) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 6 surrounding this LPA SNP, other SNPs in a 442 kb region surrounding rs3798220 (between rs9355797and rs1950562) were genotyped and analyzed. This region of 442 kb included all the SNPs with r²>0.2 with rs3798220 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 18.
• In a further analysis of SNPs in this 442 kb region surrounding rs3798220, SNPs were analyzed for association with MI risk using a meta-analysis of two case-control studies of MI, the UCSF1 and USCF2 studies. As indicated in the preceding paragraph, the UCSF1 study included 762 MI cases and 857 controls. The UCSF2 study included 579 MI cases and 1159 controls. In both the UCSF1 and UCSF2 studies, cases had a confirmed history of MI and controls had no history of CHD. A meta-analysis of the UCSF1 and UCSF2 studies was also used to analyze whether these SNPs are also associated with Lp(a) levels (Lpa level was transformed to Log10Lpa). SNPs that were significantly associated (p-value of <0.1) with both MI risk and Lp(a) levels in the meta-analysis of the UCSF1 and UCSF2 studies are provided in Table 19.
Example 4: SNPs (From a Functional Genome Scan) Associated with CVD in Two Studies
• SNPs identified in a functional genome scan (FGS) were analyzed for their association with CVD, particularly MI. For these SNPs, genetic data from two case-control studies of MI were analyzed without stratification. In one study, UCSF1, there were 762 cases and 857 controls. In the second study, UCSF2, there were 579 cases and 1159 controls. In both studies, cases had a confirmed history of MI and controls had no history of CHD. SNPs showing significant (p-value of <0.1) association with MI risk in both studies are provided in Table 20.
Example 5: SNPs Associated with Response to Statin Therapy and With Risk for CVD in the CARE Study
• The CARE (“Cholesterol and Recurrent Events”) study, which is a randomized multicentral double-blinded trial of secondary prevention of MI with pravastatin (Pravachol®) in individuals who have previously had an MI, is described in Sacks et al. (1991) Am. J. Cardiol. 68: 1436-1446 and Sacks et al. (1996) New England Journal of Medicine 335: 1001-1009. The CARE trial, including an analysis of SNPs therein, is also described in lakoubova et al., “Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials”, J Am Coll Cardiol. 2008 Jan. 29; 51(4):435-43.
• A well-documented MI was one of the enrollment criteria for entry into the CARE study. Patients were enrolled in the CARE trial from 80 participating study centers. Men and post-menopausal women were eligible for the trial if they had had an acute MI between 3 and 20 months prior to randomization, were 21 to 75 years of age, and had plasma total cholesterol levels of less than 240 mg/deciliter, LDL cholesterol levels of 115 to 174 mg/deciliter, fasting triglyceride levels of less than 350 mg/deciliter, fasting glucose levels of no more than 220 mg/deciliter, left ventricular ejection fractions of no less than 25%, and no symptomatic congestive heart failure. Patients were randomized to receive either 40 mg of pravastatin once daily or a matching placebo. The primary endpoint of the CARE trial was death from a coronary event or nonfatal MI and the median duration of follow-up was 5.0 years (range, 4.0 to 6.2 years). For the study of CARE described in this Example and shown in Tables 21-22, two endpoints were investigated: the primary endpoint of CARE (a composite endpoint of fatal coronary event or nonfatal MI, and identified as “endpt1” in the Endpoint column of Tables 21-22) and a composite endpoint of confirmed fatal or nonfatal MI (identified as “rmi” in the Endpoint column of Tables 21-22).
• Table 21 provides SNPs associated with reduction of CHD risk, particularly risk for MI and recurrent MI, by Pravastatin in the CARE study, and Table 22 provides SNPs associated with risk of CHD, particularly risk for MI and recurrent MI, in the placebo arm of the CARE study. The SNPs provided in Table 22 are a subset of the SNPs provided in Table 21; thus, the SNPs provided in Table 22 are associated with both increased CHD risk as well as reduction of CHD risk by statin treatment (e.g., Pravastatin).
• Specifically, Table 21 provides SNPs for which the effect of pravastatin on the primary endpoint of the CARE study (identified as “endpt1” in the Endpoint column) or the recurrent MI endpoint (identified as “rmi” in the Endpoint column) was analyzed by genotype subgroups and for which pravastatin reduced risk in one genotype subgroup but not in another (P-interaction between statin treatment and genotype for the enpdpoint<0.1).
• Table 22 provides a subset of SNPs from Table 21 that were associated (p<0.1) with time to occurrence of first event, either the CARE primary endpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebo group of the CARE study. In Table 22, the HR (including lower and upper confidence intervals) and p-values indicated for each SNP correspond to Allele 1 (Allele 2 is the reference allele, which is considered to have HR=1).
• HR stands for Hazard Ratio, which is a concept similar to Odds Ratio (OR). The HR in event-free survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For examples, HR describes the likelihood of developing MI based on comparison of rate of coronary events between carriers of a certain allele and noncarriers of the allele; therefore, HR=1.5 would mean that carriers of the allele have 50% higher risk of coronary events during the study follow-up than non-carriers. HR can also describe the effect of statin therapy on coronary events based on comparison of the rate of coronary events between patients treated with statin and patients treated with placebo in subgroups defined by SNP genotype; therefore, HR=0.5 would mean that, for example, carriers of a certain allele had a 50% reduction of coronary events by statin therapy as compared to placebo. In Table 21, p-interaction values were calculated. An interaction (or effect modification) is formed when a third variable modifies the relation between an exposure and outcome. A p-interaction<0.1 indicates that a third variable (genotype) modifies the relation between an exposure (statin treatment) and outcome (CARE primary endpoint or recurrent MI). Genotype and drug interaction is present when the effect of statins (incidence rate of disease in statin-treated group, as compared to placebo) differs in patients with different genotypes.
Example 6: Calculated Linkage Disequilibrium (LD) SNPs Associated with CVD
• Another investigation was conducted to identify additional SNPs that are calculated to be in linkage disequilibrium (LD) with certain “interrogated SNPs” that have been found to be associated with CVD (particularly CHD, especially MI, or hypertension), as described herein and shown in the tables. The interrogated SNPs are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 6. The methodology is described earlier in the instant application. To summarize briefly, the power threshold (T) was set at an appropriate level, such as 51%, for detecting disease association using LD markers. This power threshold is based on equation (31) above, which incorporates allele frequency data from previous disease association studies, the predicted error rate for not detecting truly disease-associated markers, and a significance level of 0.05. Using this power calculation and the sample size, a threshold level of LD, or r² value, was derived for each interrogated SNP (r_T ², equations (32) and (33) above). The threshold value r_T ² is the minimum value of linkage disequilibrium between the interrogated SNP and its LD SNPs possible such that the non-interrogated SNP still retains a power greater or equal to T for detecting disease association.
• Based on the above methodology, LD SNPs were found for the interrogated SNPs. Several exemplary LD SNPs for the interrogated SNPs are listed in Table 6; each LD SNP is associated with its respective interrogated SNP. Also shown are the public SNP IDs (rs numbers) for the interrogated and LD SNPs, when available, and the threshold r² value and the power used to determine this, and the r² value of linkage disequilibrium between the interrogated SNP and its corresponding LD SNP. As an example in Table 6, the interrogated SNP rs2145270 (hCV10048483) was calculated to be in LD with rs1000972 (hCV10048484) at an r² value of 0.9242, based on a 51% power calculation, thus establishing the latter SNP as a marker associated with CVD as well.
• In general, the threshold r_T ² value can be set such that one of ordinary skill in the art would consider that any two SNPs having an r² value greater than or equal to the threshold r_T ² value would be in sufficient LD with each other such that either SNP is useful for the same utilities, such as determing an individual's risk for CVD such as CHD (particularly MI) or hypertension. For example, in various embodiments, the threshold r_T ² value used to classify SNPs as being in sufficient LD with an interrogated SNP (such that these LD SNPs can be used for the same utilities as the interrogated SNP, for example) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r² value in-between these values). Threshold r_T ² values may be utilized with or without considering power or other calculations.
• All publications and patents cited in this specification are herein incorporated by reference in their entirety. Modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims.)

• TABLE 5
  		Primer 1 (Allele-	Primer 2 (Allele-
  Marker	Alleles	Specific Primer)	Specific Primer)	Common Primer
  hCV10048483	C/T	ACAGCGTTTGACACTTCG	AACAGCGTTTGACACTTCA	GAAACTAGGAGCAGAG
  		(SEQ ID NO: 4007)	(SEQ ID NO: 4008)	GAGAGACTA (SEQ ID
  				NO: 4009)
  hCV1026586	A/G	GTCCAGCTTAATAATTAAC	TCCAGCTTAATAATTAACT	GCCATGAGCTCAT
  		TTGTCAAATT	TGTCAAATC	TGCCTACAA
  		(SEQ ID NO: 4010)	(SEQ ID NO: 4011)	(SEQ ID NO: 4012)
  hCV1030264	A/G	AGGTAGATATCGTGGCTAAGAT	GGTAGATATCGTGGCTAAGAC	CGTCTTCTCGGATGTCATAGTGC
  		(SEQ ID NO: 4013)	(SEQ ID NO: 4014)	(SEQ ID
  				NO: 4015)
  hCV1116794	A/G	GTGAGTTCTCAGATGGTTGA	TGAGTTCTCAGATGGTTGG	GCTTCAAGCTGTTGACAGTG
  		(SEQ ID NO: 4016)	(SEQ ID NO: 4017)	(SEQ ID NO: 4018)
  hCV11170747	A/G	AATTTTTCATTCTGCATGTGTT	AATTTTTCATTCTGCATGTGTC	CCAGGGCTCTTTCAAGATAGTA
  		(SEQ ID NO: 4019)	(SEQ ID NO: 4020)	(SEQ ID NO: 4021)
  hCV11181829	C/T	GATGGAGTTTTGAGGAACC	CGATGGAGTTTTGAGGAACT	CCCTGGGCAGAATCAGA
  		(SEQ ID NO: 4022)	(SEQ ID NO: 4023)	(SEQ ID NO: 4024)
  hCV11225994	A/G	TCCCAATCCCAGGACA	CCCAATCCCAGGACG	TGACATTGCACTCTCAAATATTT
  		(SEQ ID NO: 4025)	(SEQ ID NO: 4026)	(SEQ ID
  				NO: 4027)
  hCV11231076	C/T	AGTCATGGTGGACGGTG	CAGTCATGGTGGACGGTA	CTTGGTGCTGTCCTCACTGTAGTA
  		(SEQ ID NO: 4028)	(SEQ ID NO: 4029)	(SEQ ID NO: 4030)
  hCV11276368	C/T	CGCGGAGTGTCAAGAGG	CGCGGAGTGTCAAGAGA	ACCTTGGGCAAAAAATACAT
  		(SEQ ID NO: 4031)	(SEQ ID NO: 4032)	(SEQ ID NO: 4033)
  hCV11315168	C/G	GTTGTTTGCTTCATCTCTGC	GTTGTTTGCTTCATCTCTGG	AGTGCTGGGCTCAAGAAC
  		(SEQ ID NO: 4034)	(SEQ ID NO: 4035)	(SEQ ID NO: 4036)
  hCV11315171	C/T	ATTTCTGAATAACTGAAGTTGGTC	ATTTCTGAATAACTGAAGTTGGTT	CCCTACCTGGGTTATCAGTAAT
  		(SEQ ID NO: 4037)	(SEQ ID NO: 4038)	(SEQ ID NO: 4039)
  hCV11398434	C/T	AATGAAATCTAGGAATAGTGACCAC	CAATGAAATCTAGGAATAGTGACCAT	CTTCAGCCCAAGAGTTTGAGACTA
  		(SEQ ID NO: 4040)	(SEQ ID NO: 4041)	(SEQ ID NO: 4042)
  hCV11398437	C/T	AGAGTATGTGTAATTAAGTCGCTAC	AAGAGTATGTGTAATTAAGTCGCTAT	ACTGAGGATGAGTAATTATGT
  		(SEQ ID NO: 4043)	(SEQ ID NO: 4044)	CTTATTAGGACCATAG
  				(SEQ ID NO: 4045)
  hCV11433557	G/C	TGATGAGTGTCGAAATGGAG	TGATGAGTGTCGAAATGGAG	ACCGGTTCTGCTTTGATAAC
  		(SEQ ID NO: 4046)	(SEQ ID NO: 4047)	(SEQ ID NO: 4048)
  hCV11438723	C/T	ACGCGTGTCTTTCTCAC	ACGCGTGTCTTTCTCAT	AAGTTACTTAAAATCTGCT
  		(SEQ ID NO: 4049)	(SEQ ID NO: 4050)	TTTTCTTAG
  				(SEQ ID NO: 4051)
  hCV11446935	G/T	GGCTGAAATTATTCCAATAAAGGAC	GGCTGAAATTATTCCAATAAAGGAA	ACCAGGCTGTTGACCTTGCTATAA
  		(SEQ ID NO: 4052)	(SEQ ID NO: 4053)	(SEQ ID
  				NO: 4054)
  hCV11461296	C/G	GACTGAGGCCCACGC	GACTGAGGCCCACGG	GGGTCTGCAGGTTAACAACA
  		(SEQ ID NO: 4055)	(SEQ ID NO: 4056)	(SEQ ID NO: 4057)
  hCV11466079	A/G	CCCATACCCAAGGAACCTT	CCCATACCCAAGGAACCTC	GGATCAGCCAAGCCAGACTT
  		(SEQ ID NO: 4058)	(SEQ ID NO: 4059)	(SEQ ID NO: 4060)
  hCV11466848	A/G	CTGGACTTCTGGGTCCT	TGGACTTCTGGGTCCC	CAAGAAGCTGAGCGAGTGTCT
  		(SEQ ID NO: 4061)	(SEQ ID NO: 4062)	(SEQ ID NO: 4063)
  hCV11504800	A/T	TAACAATTTGGTTTATATCCTCCCT	ACAATTTGGTTTATATCCTCCCA	CAGCTCTACATAGTATCCTGGA
  		(SEQ ID NO: 4064)	(SEQ ID NO: 4065)	GAGAC
  				(SEQ ID NO: 4066)
  hCV11513719	C/T	TCCTCCGGTGTCAGTTTAG	TCCTCCGGTGTCAGTTTAA	GCAGTGGCCAGGGTTCAT
  		(SEQ ID NO: 4067)	(SEQ ID NO: 4068)	(SEQ ID NO: 4069)
  hCV11568668	A/G	CTTTCACTCACTCAACACATACTTA	TTCACTCACTCAACACATACTTG	GCTCAGTTGGGAGATGTGTAGGTA
  		(SEQ ID NO: 4070)	(SEQ ID NO: 4071)	(SEQ ID
  				NO: 4072)
  hCV11592758	T/C	CATCCAACAGCTCTTCTATCAT	CATCCAACAGCTCTTCTATCAC	CAAACATCCGAGGACAAG
  		(SEQ ID NO: 4073)	(SEQ ID NO: 4074)	(SEQ ID NO: 4075)
  hCV11623551	C/T	ACTCTTTGATGGCAACCATG	TTAACTCTTTGATGGCAACCATA	GGTTTTAAGCCAGCACTCTTAGACT
  		(SEQ ID NO: 4076)	(SEQ ID NO: 4077)	(SEQ ID
  				NO: 4078)
  hCV11628130	T/A	CTGCCCTCTTTTTAGCAGA	CTGCCCTCTTTTTAGCAGT	CCCTTTCTCATTCATTCATTTT
  		(SEQ ID NO: 40/9)	(SEQ ID NO: 4080)	(SEQ ID NO: 4081)
  hCV11642651	C/T	AAGGATGGCCTCATCAG	AAGGATGGCCTCATCAA	CCAGGATGGAGATGAAGAGA
  		(SEQ ID NO: 4082)	(SEQ ID NO: 4083)	(SEQ ID NO: 4084)
  hCV11678789	G/T	CCACTGAAATGCTACTTTGAGTAAC	CCACTGAAATGCTACTTTGAGTAAA	AGACAATCTGAGACATGCGAAGACT
  		(SEQ ID NO: 4085)	(SEQ ID NO: 4086)	(SEQ ID
  				NO: 4087)
  hCV11688401	A/G	CCCTTTCCCAGGCTTATT	CCCTTTCCCAGGCTTATC	CCTCAACCAGGAAGTCAGAG
  		(SEQ ID NO: 4088)	(SEQ ID NO: 4089)	(SEQ ID NO: 4090)
  hCV11689916	A/T	TGTGAGTGGGCCTTCACT	GTGAGTGGGCCTTCACA	GGAGCCCCGCTTCAT
  		(SEQ ID NO: 4091)	(SEQ ID NO: 4092)	(SEQ ID NO: 4093)
  hCV11697322	A/G	CAGTTCGTGCTATTGAGAAAAT	CAGTTCGTGCTATTGAGAAAAC	CAAAGAAAAACAGATCACACAGAT
  		(SEQ ID NO: 4094)	(SEQ ID NO: 4095)	(SEQ ID
  				NO: 4096)
  hCV11703905	C/T	GCACAGAAAGCCGTGAG	GCACAGAAAGCCGTGAA	CTGTAAGCTCCTCTGGTTCAG
  		(SEQ ID NO: 4097)	(SEQ ID NO: 4098)	(SEQ ID NO: 4099)
  hCV11761245	C/T	ACACACTTCACAATGGACG	CACACACTTCACAATGGACA	CAGTAAACCTGGCACTCTTCAGTAGT
  		(SEQ ID NO: 4100)	(SEQ ID NO: 4101)	(SEQ ID
  				NO: 4102)
  hCV11764545	G/T	CGAAGCTTCCGAGGAAG	CGAAGCTTCCGAGGAAT	GACACCGGACGAGAGAGAC
  		(SEQ ID NO: 4103)	(SEQ ID NO: 4104)	(SEQ ID NO: 4105)
  hCV11765753	A/G	GAGAAAAAAGAACAGATGTCCTT	GAGAAAAAAGAACAGATGTCCTC	TGATGCCTCTCAGCATTTATAC
  		(SEQ ID NO: 4106)	(SEQ ID NO: 4107)	(SEQ ID NO: 4108)
  hCV11846435	C/T	GCTGGGAACCTCTATCCC	GCTGGGAACCTCTATCCT	GGGCTCATGAGGAAAGTTTATGTG
  		(SEQ ID NO: 4109)	(SEQ ID NO: 4110)	(SEQ ID
  				NO: 4111)
  hCV11854426	C/T	CATAATGATGTTGGTAGGGTCG	CATAATGATGTTGGTAGGGTCA	CCAGATTGATTCATGCTCCTCTCAC
  		(SEQ ID NO: 4112)	(SEQ ID NO: 4113)	(SEQ ID
  				NO: 4114)
  hCV11856381	A/G	CAATGGTGGGCATGTCTTAT	AATGGTGGGCATGTCTTAC	GAGGGCTAAAGGAAAGAGGTGTTCT
  		(SEQ ID NO: 4115)	(SEQ ID NO: 4116)	(SEQ ID
  				NO: 4117)
  hCV11864162	A/C	CCCTTTGCCTTGTCGTT	CCCTTTGCCTTGTCGTG	CACTGCACCAGGCCTAGAAATAC
  		(SEQ ID NO: 4118)	(SEQ ID NO: 4119)	(SEQ ID
  				NO: 4120)
  hCV1188731	C/T	GGCAGATAGTAGCTGTTCAATAAAC	GGCAGATAGTAGCTGTTCAATAAAT	TTTGGGTAGCAGATCAC
  		(SEQ ID NO: 4121)	(SEQ ID NO: 4122)	TTCATTAATCTGA (SEQ
  				ID NO: 4123)
  hCV1188735	C/T	CTTGCTCTGATAAGAACTTTACAAC	CCTTGCTCTGATAAGAACTTTACAAT	CTGCCGTGGCCTTTCAAAG
  		(SEQ ID NO: 4124)	(SEQ ID NO: 4125)	(SEQ ID NO: 4126)
  hCV1188747	C/G	TGAAAATGTTCCTGAGCTATGG	TGAAAATGTTCCTGAGCTATGG	ACTATCACCCAGAAGGCGATCATAC
  		(SEQ ID NO: 4127)	(SEQ ID NO: 4128)	(SEQ ID
  				NO: 4129)
  hCV11955747	A/C	AAAGGGAAGGAGGTTACTTACT	AGGGAAGGAGGTTACTTACG	TCCTCTGTGGAGAGGGATAC
  		(SEQ ID NO: 4130)	(SEQ ID NO: 4131)	(SEQ ID NO: 4132)
  hCV11960994	A/G	TTTGTAAACACACAGAGATGATAAT	TTTGTAAACACACAGAGATGATAAC	TTTCCGCTCGACATGTAA
  		(SEQ ID NO: 4133)	(SEQ ID NO: 4134)	(SEQ ID NO: 4135)
  hCV11972326	C/G	TTCTTTTAAAGGATTGGTAAACTC	TTCTTTTAAAGGATTGGTAAACTG	AGAGCAGAACGAGGTTTTATTT
  		(SEQ ID NO: 4136)	(SEQ ID NO: 4137)	(SEQ ID NO: 4138)
  hCV12020339	G/T	GGACCCCCGAAGGC	TGGACCCCCGAAGGA	GGCCCCAACAGTTGACTG
  		(SEQ ID NO: 4139)	(SEQ ID NO: 4140)	(SEQ ID NO: 4141)
  hCV12022345	A/T	AGTGGCCTCATCCTCCT	GTGGCCTCATCCTCCA	GAACGCTTACGAGCCTTATC
  		(SEQ ID NO: 4142)	(SEQ ID NO: 4143)	(SEQ ID NO: 4144)
  hCV12034662	A/G	GGGGCTATGTAGACTACATCTTTA	GGGCTATGTAGACTACATCTTTG	TTCAACAATGCGTTGGCAAGAGAT
  		(SEQ ID NO: 4145)	(SEQ ID NO: 4146)	(SEQ ID
  				NO: 4147)
  hCV12107274	C/T	TGATGCTAATCTGTTCTCTGTG	TCTGATGCTAATCTGTTCTCTGTA	ATAACAAGAGGAAGGAGATCAGA
  		(SEQ ID NO: 4148)	(SEQ ID NO: 4149)	(SEQ ID
  				NO: 4150)
  hCV12108469	A/G	TCGTGTCTACCTTAGGGTACA	CGTGTCTACCTTAGGGTACG	CGTATGGCTTCAGGATGTC
  		(SEQ ID NO: 4151)	(SEQ ID NO: 4152)	(SEQ ID NO: 4153)
  hCV1239369	A/C	GAAGATGTTACTCCTAAT	AAGATGTTACTCCTAATA	GTTGTACCCTCATTGT
  		ATCATACAGT	TCATACAGG	GACATTAGGT
  		(SEQ ID	(SEQ ID NO: 4155)	(SEQ ID
  		NO: 4154)		NO: 4156)
  hCV1243283	A/G	TTATTCCTAGTTCCAATGAAAGAT	TTATTCCTAGTTCCAATGAAAGAC	GCCTCTTGGGAGTACTCACTT
  		(SEQ ID NO: 4157)	(SEQ ID NO: 4158)	(SEQ ID NO: 4159)
  hCV1253630	A/G	TCGCAGGTGTCCCTA	CGCAGGTGTCCCTG	CCCCATCCCTTCTCA
  		(SEQ ID NO: 4160)	(SEQ ID NO: 4161)	(SEQ ID NO: 4162)
  hCV1323634	C/T	GAAGTGAAATAATGGTTCAGCATAC	GAAGTGAAATAATGGTTCAGCATAT	CTGCATCTGTTGAGAT
  		(SEQ ID NO: 4163)	(SEQ ID NO: 4164)	TATTGTATGACGTT
  				(SEQ ID NO: 4165)
  hCV1323669	A/G	GTGTTATACTGTATCACTCTTC	TGTTATACTGTATCACTCT	GGGGGCGGAACT
  		TTTTCTAA	TCTTTTCTAG	TAGACA
  		(SEQ ID	(SEQ ID	(SEQ ID NO: 4168)
  		NO: 4166)	NO: 4167)
  hCV1345898	C/T	CAGTTTTCCATGGGTTCTACTAC	CAGTTTTCCATGGGTTCTACTAT	TTATGAAATGGTACAGACAAGTGAT
  		(SEQ ID NO: 4169)	(SEQ ID NO: 4170)	(SEQ ID
  				NO: 4171)
  hCV1361979	A/G	CCAGTTTTGGTGTCAACTAGAAA	CCAGTTTTGGTGTCAACTAGAAG	TTGCAACCTGAAAAACATAACTA
  		(SEQ ID NO: 4172)	(SEQ ID NO: 4173)	(SEQ ID
  				NO: 4174)
  hCV1366867	A/G	GGAGCCAGGCCTACAT	GGAGCCAGGCCTACAC	CGCCTCGACGAGATTCT
  		(SEQ ID NO: 4175)	(SEQ ID NO: 4176)	(SEQ ID NO: 4177)
  hCV1375141	C/T	CCTTCGGAGTTGCACAG	CCTTCGGAGTTGCACAA	TTTTTGGTGGGTTTCTCTGTA
  		(SEQ ID NO: 4178)	(SEQ ID NO: 4179)	(SEQ ID NO: 4180)
  hCV1415464	C/G	CCCTGGGGGTCTTTC	CCCTGGGGGTCTTTG	CCGTGGCCTCTGTGATT
  		(SEQ ID NO: 4181)	(SEQ ID NO: 4182)	(SEQ ID NO: 4183)
  hCV1449414	T/C	ACACACATATGGTGGTTCATAAT	CACACATATGGTGGTTCATAAC	CATGTCCCAGCTCTTCTTG
  		(SEQ ID NO: 4184)	(SEQ ID NO: 4185)	(SEQ ID NO: 4186)
  hCV1449416	T/A	TATGCAAGGTGTTGTTATAGATTT	GTATGCAAGGTGTTGTTATAGATTA	GCGTTGTAACTGAGTTCATTATTC
  		(SEQ ID NO: 4187)	(SEQ ID NO: 4188)	(SEQ ID NO: 4189)
  hCV1463112	C/T	TTCAAGCTATTTGTAGTTCCTAGAG	CTTCAAGCTATTTGTAGTTCCTAGAA	GGTGTGGCCTTCTTTGGAAGATC
  		(SEQ ID NO: 4190)	(SEQ ID NO: 4191)	(SEQ ID
  				NO: 4192)
  hCV1463184	C/T	GGTTAAATGACACTCTT	GGTTAAATGACACTCT	GTTTCAGAAAGATTTGTC
  		TGGGG	TTGGGA	AGGACCACT
  		(SEQ ID NO: 4193)	(SEQ ID NO: 4194)	(SEQ ID
  				NO: 4195)
  hCV1463222	C/T	TGTTTCTCCCACATATTCACATAC	CTGTTTCTCCCACATATTCACATAT	CGCTACATCACTCAGCTCATGAAA
  		(SEQ ID NO: 4196)	(SEQ ID NO: 4197)	(SEQ ID
  				NO: 4198)
  hCV1463224	C/T	CAACTCACACGGGAAGAC	CAACTCACACGGGAAGAT	GTGAATATGTGGGAGAAACAG
  		(SEQ ID NO: 4199)	(SEQ ID NO: 4200)	CACTAG
  				(SEQ ID
  				NO: 4201)
  hCV1463226	C/T	ATTTCCTCCCTCACATGATAC	ATTTCCTCCCTCACATGATAT	TCAAAGAATGAAGAGTGAAGACA
  		(SEQ ID NO: 4202)	(SEQ ID NO: 4203)	(SEQ ID
  				NO: 4204)
  hCV1488444	G/T	TCAACAGAATGCCATGAGC	GTCAACAGAATGCCATGAGA	CAAGGCAGAAGTAGTTGTCCAACAG
  		(SEQ ID NO: 4205)	(SEQ ID NO: 4206)	(SEQ ID
  				NO: 4207)
  hCV1489995	C/G	GAGGCGAAAGGAACAGAG	GAGGCGAAAGGAACAGAG	GCGTGCTGAGGAGTAATGTAC
  		(SEQ ID NO: 4208)	(SEQ ID NO: 4209)	(SEQ ID NO: 4210)
  hCV1550877	C/T	GGTCCAAATAGACTAACT	GGTCCAAATAGACTAACTT	CCCACACAACATACAATTT
  		TTAAGTGAC	TAAGTGAT	ACAAATGC
  		(SEQ ID	(SEQ ID NO: 4212)	(SEQ ID
  		NO: 4211)		NO: 4213)
  hCV1552894	A/G	CAGATTCAGCCTCCCAA	CAGATTCAGCCTCCCAG	GCAGTTGGAAATCTGAATTTC
  		(SEQ ID NO: 4214)	(SEQ ID NO: 4215)	(SEQ ID NO: 4216)
  hCV1552900	A/G	GGGATGGAAGAGCTTCA	GGGATGGAAGAGCTTCG	CTGCAGCCTTCCTCTGAC
  		(SEQ ID NO: 4217)	(SEQ ID NO: 4218)	(SEQ ID NO: 4219)
  hCV15746640	A/G	GAAACGGCTGGTTTGTGT	AACGGCTGGTTTGTGC	TCCAATCTACCTTTTCCTTGTATT
  		(SEQ ID NO: 4220)	(SEQ ID NO: 4221)	(SEQ ID
  				NO: 4222)
  hCV15752705	C/G	GCCTCCCCTGCTGC	GGCCTCCCCTGCTGG	AGGTCCCTTCTGCTGTAATG
  		(SEQ ID NO: 4223)	(SEQ ID NO: 4224)	(SEQ ID NO: 4225)
  hCV15752716	C/T	ACGCTGCTGTTCCG	CACGCTGCTGTTCCA	CAGACAGACAACAATTCAGAAGAA
  		(SEQ ID NO: 4226)	(SEQ ID NO: 4227)	(SEQ ID
  				NO: 4228)
  hCV15758290	G/A	GTCACACACCCAGGAGC	GGTCACACACCCAGGAGT	GGATGATTGCCATAATGAGTC
  		(SEQ ID NO: 4229)	(SEQ ID NO: 4230)	(SEQ ID NO: 4231)
  hCV15760070	A/T	TGTCCAGATCCACATAGAACA	TTGTCCAGATCCACATAGAACT	CTTTATGCAGCGGACCAT
  		(SEQ ID NO: 4232)	(SEQ ID NO: 4233)	(SEQ ID NO: 4234)
  hCV15770510	C/T	ACGGCATCTTCTATCCG	CACGGCATCTTCTATCCA	CCAGCTGGTGGTGAGTG
  		(SEQ ID NO: 4235)	(SEQ ID NO: 4236)	(SEQ ID NO: 4237)
  hCV15851335	C/T	GATGGCATGGATGGC	GGATGGCATGGATGGT	GCAGGATGTGCTGTGATTAT
  		(SEQ ID NO: 4238)	(SEQ ID NO: 4239)	(SEQ ID NO: 4240)
  hCV15851779	A/G	CAACCTGACATGGAAGAAAT	CAACCTGACATGGAAGAAAC	GATGTGGTGGGATTTGACAT
  		(SEQ ID NO: 4241)	(SEQ ID NO: 4242)	(SEQ ID NO: 4243)
  hCV15870728	C/T	GAGAGAGAACAGCCAGAC	GAGAGAGAACAGCCAGAT	GCATCCCAGGTCAAGGTA
  		(SEQ ID NO: 4244)	(SEQ ID NO: 4245)	(SEQ ID NO: 4246)
  hCV15871150	A/G	CCCAAATTCTGCATAGCATAA	CCCAAATTCTGCATAGCATAG	GTGGGCTCGGGTCTCTA
  		(SEQ ID NO: 4247)	(SEQ ID NO: 4248)	(SEQ ID NO: 4249)
  hCV15874689	A/G	TGGAAAGCCTCAAGTCT	GGAAAGCCTCAAGTCC	TTCTAGAGGTGGTCAG
  		(SEQ ID NO: 4250)	(SEQ ID NO: 4251)	CTAATACTT
  				(SEQ ID
  				NO: 4252)
  hCV15876011	T/G	ACCATCAGTTACCTTCATGACT	CATCAGTTACCTTCATGACG	GCGGACCACCTGTTAATC
  		(SEQ ID NO: 4253)	(SEQ ID NO: 4254)	(SEQ ID NO: 4255)
  hCV15882274	G/A	CATGGAGATCCAAGTCG	ACATGGAGATCCAAGTCA	GACTCAGGCAGGACAACC
  		(SEQ ID NO: 4256)	(SEQ ID NO: 4257)	(SEQ ID NO: 4258)
  hCV15885004	A/G	CTCCCCTACTCTGCTCATATAT	CTCCCCTACTCTGCTCATATAC	CATTCTCCCCACCAGGCATTTAT
  		(SEQ ID NO: 4259)	(SEQ ID NO: 4260)	(SEQ ID
  				NO: 4261)
  hCV15892430	C/T	ACTGAGAGCTTGTCCTCAG	ACTGAGAGCTTGTCCTCAA	CACACCCAGAGACCACAGG
  		(SEQ ID NO: 4262)	(SEQ ID NO: 4263)	(SEQ ID NO: 4264)
  hCV15954277	A/G	TGTCGGTAAACATGGCA	GTCGGTAAACATGGCG	GGTGGGTGGTCTGACTCTC
  		(SEQ ID NO: 4265)	(SEQ ID NO: 4266)	(SEQ ID NO: 4267)
  hCV15954645	A/T	CTGATGGTATTTTACAGTGGATCA	CTGATGGTATTTTACAGTGGATCT	AAGACGCAACGAGCTTTGTGT
  		(SEQ ID NO: 4268)	(SEQ ID NO: 4269)	(SEQ ID NO: 4270)
  hCV15955388	C/T	TGCATTACTCGGACCC	CTGCATTACTCGGACCT	TGCCCGCACCTTGTC
  		(SEQ ID NO: 4271)	(SEQ ID NO: 4272)	(SEQ ID NO: 4273)
  hCV15963535	C/G	GTTGCTCATAGTTGCTGGC	GTTGCTCATAGTTGCTGGG	CAGCATCTTCGACAGAGACA
  		(SEQ ID NO: 4274)	(SEQ ID NO: 4275)	(SEQ ID NO: 4276)
  hCV15963962	A/G	TACTGTCCCGTGTTCCA	CTGTCCCGTGTTCCG	CTCTCCCAGAGCCCTCTAG
  		(SEQ ID NO: 4277)	(SEQ ID NO: 4278)	(SEQ ID NO: 4279)
  hCV15963994	G/T	GCTGCGTTTCTACTCTGC	TGCTGCGTTTCTACTCTGA	ACTCATGCGCATGCACATAAACA
  		(SEQ ID NO: 4280)	(SEQ ID NO: 4281)	(SEQ ID
  				NO: 4282)
  hCV15965796	C/G	CGCCCTGCACTTTCAC	CGCCCTGCACTTTCAG	CCGTGCTCTACTGCTTCTCTA
  		(SEQ ID NO: 4283)	(SEQ ID NO: 4284)	(SEQ ID NO: 4285)
  hCV15967490	C/T	TGGAGGGTCCAACTCATAAC	TGGAGGGTCCAACTCATAAT	GGGATTGCTCAGCATCTCCTTAAAT
  		(SEQ ID NO: 4286)	(SEQ ID NO: 4287)	(SEQ ID
  				NO: 4288)
  hCV15973230	A/G	TCACTGATGTCAATGAACACT	ACTGATGTCAATGAACACC	CCCATCCCAGAGTTCTTGTC
  		(SEQ ID NO: 4289)	(SEQ ID NO: 4290)	(SEQ ID NO: 4291)
  hCV1600754	C/T	ATTTCCCTGGGAAGACTTC	ATTTCCCTGGGAAGACTTT	CTAGTGGTGGAAGGAAATGTTA
  		(SEQ ID NO: 4292)	(SEQ ID NO: 4293)	(SEQ ID
  				NO: 4294)
  hCV1603697	C/T	CGGCCTGCGTGGAC	CGGCCTGCGTGGAT	GCCCAGGGCGTGTTCT
  		(SEQ ID NO: 4295)	(SEQ ID NO: 4296)	(SEQ ID NO: 4297)
  hCV16044337	A/G	TCCGGGTGCACGTATA	CGGGTGCACGTATG	TGGAGAGTGTTTGCTCATCTAC
  		(SEQ ID NO: 4298)	(SEQ ID NO: 4299)	(SEQ ID NO: 4300)
  hCV16047108	A/G	TGTTTTCATCCACTTGAACTGT	TTTTCATCCACTTGAACTGC	CAATTTTGGCTCCCTTAAAAG
  		(SEQ ID NO: 4301)	(SEQ ID NO: 4302)	(SEQ ID NO: 4303)
  hCV16065831	C/T	CTCCTGACTGTGAACAACTTATC	CTCCTGACTGTGAACAACTTATT	CCCCCAGTTGTGCATACAC
  		(SEQ ID NO: 4304)	(SEQ ID NO: 4305)	(SEQ ID NO: 4306)
  hCV16140621	A/T	AGCTGAAAGGAGAAGTCAGT	AGCTGAAAGGAGAAGTCAGA	CCCTGCTACGAAGGTGGAATATCT
  		(SEQ ID NO: 4307)	(SEQ ID NO: 4308)	(SEQ ID
  				NO: 4309)
  hCV16172339	A/T	CTGCGGCTCCACCT	TGCGGCTCCACCA	TGGCATCTGCCATACTCA
  		(SEQ ID NO: 4310)	(SEQ ID NO: 4311)	(SEQ ID NO: 4312)
  hCV16173091	T/C	CACAGACTTGATGTTTTTGAAAGT	CAGACTTGATGTTTTTGAAAGC	TGCAAAGGAAGCAACTTCA
  		(SEQ ID NO: 4313)	(SEQ ID NO: 4314)	(SEQ ID NO: 4315)
  hCV16179493	C/T	GGGTCCGGCCACAC	GGGTCCGGCCACAT	GGGCCCCTCAGTGAAG
  		(SEQ ID NO: 4316)	(SEQ ID NO: 4317)	(SEQ ID NO: 4318)
  hCV16179599	C/T	CTGCTCTCAGAACCTCAGTC	CTGCTCTCAGAACCTCAGTT	CACTGCAGGGAAATAGAGAAA
  		(SEQ ID NO: 4319)	(SEQ ID NO: 4320)	(SEQ ID NO: 4321)
  hCV16179628	A/G	CAGGTTCACTGTTTCTCCAAT	CAGGTTCACTGTTTCTCCAAC	GAGCACATCCTTCCATTGTAA
  		(SEQ ID NO: 4322)	(SEQ ID NO: 4323)	(SEQ ID NO: 4324)
  hCV16182835	A/G	TGTTCTTCCTTATGATGATGT	GTTCTTCCTTATGATGATGC	GGCGTTCCTCTCACCTTAATA
  		(SEQ ID NO: 4325)	(SEQ ID NO: 4326)	(SEQ ID NO: 4327)
  hCV16186452	C/T	GGCACCCCCGACAG	GGCACCCCCGACAA	TCCTTATGCTCTCAGTGAAGTTC
  		(SEQ ID NO: 4328)	(SEQ ID NO: 4329)	(SEQ ID
  				NO: 4330)
  hCV16189421	C/T	GCCATCATTTGCTTCTAACAC	GCCATCATTTGCTTCTAACAT	GCTTATTTGCCAGAAAACATTT
  		(SEQ ID NO: 4331)	(SEQ ID NO: 4332)	(SEQ ID NO: 4333)
  hCV16192174	G/A	GAGCACCTTAACTATAGATGGTG	TGAGCACCTTAACTATAGATGGTA	CTTGTCAAGGCACAGAATAATT
  		(SEQ ID NO: 4334)	(SEQ ID NO: 4335)	(SEQ ID NO: 4336)
  hCV16196618	C/G	ATTAGCCCCAAAGCGTAC	ATTAGCCCCAAAGCGTAG	GCTTTAGAAGGCTGGATATTTATG
  		(SEQ ID NO: 4337)	(SEQ ID NO: 4338)	(SEQ ID
  				NO: 4339)
  hCV1639938	A/C	AGTGGAGCTTCAGGGCT	TGGAGCTTCAGGGCG	CAGTGGAGACAGAGGATGTTTAC
  		(SEQ ID NO: 4340)	(SEQ ID NO: 4341)	(SEQ ID
  				NO: 4342)
  hCV1643239	C/T	CCAGAGTCCACAGAAAGTTTC	CCAGAGTCCACAGAAAGTTTT	GAAAATAACGCAAGCAGTTTC
  		(SEQ ID NO: 4343)	(SEQ ID NO: 4344)	(SEQ ID NO: 4345)
  hCV1647371	C/T	CTGGCTGGGTCACTAACC	GCTGGCTGGGTCACTAACT	CCTCACCTGCATTCACATTT
  		(SEQ ID NO: 4346)	(SEQ ID NO: 4347)	(SEQ ID NO: 4348)
  hCV1682755	C/T	TGTTCTCAATGAATCAAAGC	CATGTTCTCAATGAATC	GTCTTCCCCATGTTC
  		TATTAC	AAAGCTATTAT	ATACTCTTGT
  		(SEQ ID NO: 4349)	(SEQ ID	(SEQ ID
  			NO: 4350)	NO: 4351)
  hCV1690777	A/G	GGCTTTACAGAAGGAAATGCT	GCTTTACAGAAGGAAATGCC	GCATGCGCTGAATTTTATATAG
  		(SEQ ID NO: 4352)	(SEQ ID NO: 4353)	(SEQ ID NO: 4354)
  hCV1729928	A/G	GGAAATTGTTGAGTGTTTGTAAAGT	GGAAATTGTTGAGTGTTTGTAAAGC	CAATGCCCAAAGTTGGCTATGATT
  		(SEQ ID NO: 4355)	(SEQ ID NO: 4356)	(SEQ ID
  				NO: 4357)
  hCV1741111	C/T	CCTCAGAATGGCCAAAAAC	CCTCAGAATGGCCAAAAAT	CCAGGCAGCCAGACTTCT
  		(SEQ ID NO: 4358)	(SEQ ID NO: 4359)	(SEQ ID NO: 4360)
  hCV1770462	A/G	GCACCTCTGGGTGAAGAATA	CACCTCTGGGTGAAGAATG	GGCACAGGCAAGTCTGATT
  		(SEQ ID NO: 4361)	(SEQ ID NO: 4362)	(SEQ ID NO: 4363)
  hCV1782711	C/T	CCACTGCTGCAAGGAGTC	CCACTGCTGCAAGGAGTT	GCAGTCATCATATGGACAACTTAC
  		(SEQ ID NO: 4364)	(SEQ ID NO: 4365)	(SEQ ID
  				NO: 4366)
  hCV1801149	A/G	GAGAGTCGCAGGGTATTTTAA	GAGAGTCGCAGGGTATTTTAG	AAAGGCCCAGGCTCTAGA
  		(SEQ ID NO: 4367)	(SEQ ID NO: 4368)	(SEQ ID NO: 4369)
  hCV1802755	C/T	CTCCTTAAGAAGAATGCCACC	TCTCCTTAAGAAGAATGCCACT	AGCCAGTTTAGCATTTACTC
  		(SEQ ID NO: 4370)	(SEQ ID NO: 4371)	TTTACAAG
  				(SEQ ID
  				NO: 4372)
  hCV1843175	A/C	CCCCGAAGCCTATGGCT	CCCGAAGCCTATGGCG	CGTCAGCACCCAACTCTG
  		(SEQ ID NO: 4373)	(SEQ ID NO: 4374)	(SEQ ID NO: 4375)
  hCV1844077	A/G	CCCTAAATGCAGAAATTGAATCTT	CCCTAAATGCAGAAATTGAATCTC	CCCTCTGAAATGCTGCTGTAACT
  		(SEQ ID NO: 4376)	(SEQ ID NO: 4377)	(SEQ ID
  				NO: 4378)
  hCV1948599	A/C	GCAGTTTGAGTATAAATTG	GCAGTTTGAGTATAAATT	CAGTGACAGATGAGTGCAGAGAAT
  		TTTGACTA (SEQ ID	GTTTGACTC	(SEQ ID
  		NO: 4379)	(SEQ ID NO: 4380)	NO: 4381)
  hCV2002654	C/G	GGAGCCCCAGGAAAG	GGAGCCCCAGGAAAG	AGAGCCCTCGGTTCTTG
  		(SEQ ID NO: 4382)	(SEQ ID NO: 4383)	(SEQ ID NO: 4384)
  hCV2038	G/A	CACGGCGGTCATGTG	CCACGGCGGTCATGTA	GGTGGAGCTTGGTTTCTCA
  		(SEQ ID NO: 4385)	(SEQ ID NO: 4386)	(SEQ ID NO: 4387)
  hCV207123	C/G	TGTAGATCATGTGGATGGATTG	AATGTAGATCATGTGGATGGATTC	CTGTCAGGCTGTCTGTAAGTCTCTAT
  		(SEQ ID NO: 4388)	(SEQ ID NO: 4389)	(SEQ ID
  				NO: 4390)
  hCV2091644	C/T	TTCTGGGGCATACAACG	CTTCTGGGGCATACAACA	AGGGACAACCCTCCATAAA
  		(SEQ ID NO: 4391)	(SEQ ID NO: 4392)	(SEQ ID NO: 4393)
  hCV2091649	A/G	CCTCAGAGTATGTGCCCA	CCTCAGAGTATGTGCCCG	GCCCGGCTGCATCTAGTT
  		(SEQ ID NO: 4394)	(SEQ ID NO: 4395)	(SEQ ID NO: 4396)
  hCV2091650	C/T	TCTCTGAGCTGAGTGCC	GTCTCTGAGCTGAGTGCT	TCCCTATCCTAACTCTCCTTGTCT
  		(SEQ ID NO: 4397)	(SEQ ID NO: 4398)	(SEQ ID
  				NO: 4399)
  hCV2091669	A/T	GTCAGTAGCGCTCACTTTT	GTCAGTAGCGCTCACTTTA	GGCTACTTAGCTGCAGTTCAAACTC
  		(SEQ ID NO: 4400)	(SEQ ID NO: 4401)	(SEQ ID
  				NO: 4402)
  hCV2091674	G/T	CCACTTAATAACAACACTACTTGC	GCCACTTAATAACAACACTACTTGA	GACTGAGCCTGTTTCCTCACCTATAA
  		(SEQ ID NO: 4403)	(SEQ ID NO: 4404)	(SEQ ID
  				NO: 4405)
  hCV2143205	A/G	TGTCGAATGGGAGTCTTCTT	TGTCGAATGGGAGTCTTCTC	CCTAGTAGTACAACGGAAGAAACAG
  		(SEQ ID NO: 4406)	(SEQ ID NO: 4407)	(SEQ ID
  				NO: 4408)
  hCV2146578	C/T	CCTCCTAGAGAAGATCTGCAC	CCTCCTAGAGAAGATCTGCAT	AAGGCCCCTCTTCTGTCT
  		(SEQ ID NO: 4409)	(SEQ ID NO: 4410)	(SEQ ID NO: 4411)
  hCV2146579	A/C	TTCCTAACAGAGGCTTGGA	TCCTAACAGAGGCTTGGC	TGCAGTGTCCCCTAGAATG
  		(SEQ ID NO: 4412)	(SEQ ID NO: 4413)	(SEQ ID NO: 4414)
  hCV2192261	C/T	CCTACCTTGAATTCACCTATCTG	CCTACCTTGAATTCACCTATCTA	CATTTCCAAATCAGAAACATGA
  		(SEQ ID NO: 4415)	(SEQ ID NO: 4416)	(SEQ ID NO: 4417)
  hCV2195496	C/T	GCACCTCACAAACACCG	TGCACCTCACAAACACCA	GCCTCTTCTGCAAATGGATGA
  		(SEQ ID NO: 4418)	(SEQ ID NO: 4419)	TATACAC
  				(SEQ ID
  				NO: 4420)
  hCV2221541	C/T	CCTGGAGTGGATGCCTTC	CCTGGAGTGGATGCCTTT	GGACAGCAGACACCTGAGC
  		(SEQ ID NO: 4421)	(SEQ ID NO: 4422)	(SEQ ID NO: 4423)
  hCV22271999	C/T	GAGCACCTTAACTATAGATGGTG	TGAGCACCTTAACTATAGATGGTA	CTTGTCAAGGCACAGAATAATT
  		(SEQ ID NO: 4424)	(SEQ ID NO: 4425)	(SEQ ID NO: 4426)
  hCV22273354	A/G	CAGGTCAGGCACAAACAT	CAGGTCAGGCACAAACAC	GAAGATGACCTGTTGAGTCAGTA
  		(SEQ ID NO: 4427)	(SEQ ID NO: 4428)	(SEQ ID
  				NO: 4429)
  hCV22274594	G/A	ACAACAGGAGCACACCG	GACAACAGGAGCACACCA	GATGCAGTCCCTTTTTCTAAA
  		(SEQ ID NO: 4430)	(SEQ ID NO: 4431)	(SEQ ID NO: 4432)
  hCV22274679	C/T	TATCGCTGGGTAAACCG	GTATCGCTGGGTAAACCA	CGACTCTGAGGAGATGGAGTAT
  		(SEQ ID NO: 4433)	(SEQ ID NO: 4434)	(SEQ ID
  				NO: 4435)
  hCV22274761	A/G	ACTCCCCCAAGATCTTCT	CCCCCAAGATCTTCC	GCTCCCCCGACAAACT
  		(SEQ ID NO: 4436)	(SEQ ID NO: 4437)	(SEQ ID NO: 4438)
  hCV22275550	C/T	CCATCTGTTCCGCCG	TCCATCTGTTCCGCCA	TTACCCAGCAGCGAAGAC
  		(SEQ ID NO: 4439)	(SEQ ID NO: 4440)	(SEQ ID NO: 4441)
  hCV22303	A/G	AGCTTGGTTGTAGCCCA	GCTTGGTTGTAGCCCG	AGGCCAGCCTCCAAATCTTTC
  		(SEQ ID NO: 4442)	(SEQ ID NO: 4443)	(SEQ ID NO: 4444)
  hCV2230606	A/G	AAATGTTGTCAACGTCCA	AATGTTGTCAACGTCCG	AGTCACTGGCAGCAATGAT
  		(SEQ ID NO: 4445)	(SEQ ID NO: 4446)	(SEQ ID NO: 4447)
  hCV2275263	A/T	GTCCATCAGCAAATTGTCTCT	GTCCATCAGCAAATTGTCTCA	CCGATGACCTGGGGACATATTAG
  		(SEQ ID NO: 4448)	(SEQ ID NO: 4449)	(SEQ ID
  				NO: 4450)
  hCV2275272	C/T	CCTTTCCTTGTCTGTCTGC	CCTTTCCTTGTCTGTCTGT	GAAGGAGGGGGAGGAATGACT
  		(SEQ ID NO: 4451)	(SEQ ID NO: 4452)	(SEQ ID NO: 4453)
  hCV2275273	A/G	AGAGGTCAGCACTTACAGTT	AGAGGTCAGCACTTACAGTC	CAAGCAAGCATAGACCAGATAT
  		(SEQ ID NO: 4454)	(SEQ ID NO: 4455)	(SEQ ID NO: 4456)
  hCV2275276	A/G	CCATTCACATACAAATCTTTCTTACT	CCATTCACATACAAATCTTTCTTACC	CCAGATGAAACTTCTTCCTGGTCATT
  		(SEQ ID NO: 4457)	(SEQ ID NO: 4458)	(SEQ ID
  				NO: 4459)
  hCV2276802	A/C	TGGCTCAAGACCAAT	TGGCTCAAGACCAAG	CCCACATCCTTGCTGATC
  		(SEQ ID NO: 4460)	(SEQ ID NO: 4461)	(SEQ ID NO: 4462)
  hCV2310409	A/T	CTCAGGGAGGGAGAGAGA	CTCAGGGAGGGAGAGAGT	ACAGCTCAGGCAGAAACTG
  		(SEQ ID NO: 4463)	(SEQ ID NO: 4464)	(SEQ ID NO: 4465)
  hCV2335281	G/T	CAGCCTAGGCAGCATTG	CAGCCTAGGCAGCATTT	CCTGGGTTCAACCTTCTGAGTAGAT
  		(SEQ ID NO: 4466)	(SEQ ID NO: 4467)	(SEQ ID
  				NO: 4468)
  hCV2485037	A/G	TGCAAGAGGACTAAGCATGA	GCAAGAGGACTAAGCATGG	GCGGCCTTGCACTCA
  		(SEQ ID NO: 4469)	(SEQ ID NO: 4470)	(SEQ ID NO: 4471)
  hCV2503034	A/C	ACGACAGGATCCTGAATGA	CGACAGGATCCTGAATGC	CCTAGCTCGTACCCACCTCT
  		(SEQ ID NO: 4472)	(SEQ ID NO: 4473)	(SEQ ID NO: 4474)
  hCV2531086	A/G	GCCCCCCTCTCTGAAGA	CCCCCCTCTCTGAAGG	CCAGTTCGTGGTATGTTCATCT
  		(SEQ ID NO: 4475)	(SEQ ID NO: 4476)	(SEQ ID NO: 4477)
  hCV2531730	T/A	CATTTGGCTATTTTTAGCTCTAAA	ACATTTGGCTATTTTTAGCTCTAAT	GCGGCTGGGTTTCTGT
  		(SEQ ID NO: 44/8)	(SEQ ID NO: 44/9)	(SEQ ID NO: 4480)
  hCV2536595	A/G	CATCCCGCGCCAT	CATCCCGCGCCAC	CCTCCAGAGAAGAAGAAGACAC
  		(SEQ ID NO: 4481)	(SEQ ID NO: 4482)	(SEQ ID
  				NO: 4483)
  hCV25472345	C/T	GGTCACAGCCAGGC	AGGTCACAGCCAGGT	CCCCAGGAATATGTAAGTTGA
  		(SEQ ID NO: 4484)	(SEQ ID NO: 4485)	(SEQ ID NO: 4486)
  hCV25472673	C/T	TGGGCTCCATCCCAC	TGGGCTCCATCCCAT	CCAATTCTTTTTCTTCTTTCAGTT
  		(SEQ ID NO: 4487)	(SEQ ID NO: 4488)	(SEQ ID
  				NO: 4489)
  hCV25473098	A/G	CACAGACTTGATGTTTTTGAAAGT	CAGACTTGATGTTTTTGAAAGC	TGCAAAGGAAGCAACTTCA
  		(SEQ ID NO: 4490)	(SEQ ID NO: 4491)	(SEQ ID NO: 4492)
  hCV25474101	C/T	GCTGCTATTTTTGTTATTA	GCTGCTATTTTTGTTATTAT	GGCCTTACCATCTCCAGAAA
  		TTATTTTCTAC	TATTTTCTAT	(SEQ ID NO: 4495)
  		(SEQ ID	(SEQ ID
  		NO: 4493)	NO: 4494)
  hCV2553030	C/T	CCGGCTTGCACTTCAC	CCGGCTTGCACTTCAT	CTTTGTGGCCGCAGTAGT
  		(SEQ ID NO: 4496)	(SEQ ID NO: 4497)	(SEQ ID NO: 4498)
  hCV2554615	C/G	GCTCAGTCATTACCTTTGCC	GCTCAGTCATTACCTTTGCG	ACTGCTCCCTCCCATTCATACAG
  		(SEQ ID NO: 4499)	(SEQ ID NO: 4500)	(SEQ ID
  				NO: 4501)
  hCV2554721	A/G	TTAATTCTTTTGGCACAGGTAGA	ATTCTTTTGGCACAGGTAGG	TGACTGGGGAGAAGTGAGAACTAGA
  		(SEQ ID NO: 4502)	(SEQ ID NO: 4503)	(SEQ ID
  				NO: 4504)
  hCV2557331	C/T	GGGGCCATTTATTCTTCTTCAC	GGGGCCATTTATTCTTCTTCAT	GGAGTGGAAGGAATGGGGATTAAAG
  		(SEQ ID NO: 4505)	(SEQ ID NO: 4506)	(SEQ ID
  				NO: 4507)
  hCV2557469	A/C	TGCTGGTGGCTTTAAAGAA	TGCTGGTGGCTTTAAAGAC	GGCAAAACCCCTTTTATTG
  		(SEQ ID NO: 4508)	(SEQ ID NO: 4509)	(SEQ ID NO: 4510)
  hCV25591528	A/G	TCCAAAAGGACCTGACAT	TCCAAAAGGACCTGACAC	GGCTGCAGAATGGAATTT
  		(SEQ ID NO: 4511)	(SEQ ID NO: 4512)	(SEQ ID NO: 4513)
  hCV25596880	C/G	CCTAGACAATAAAGATGGTCCTC	CCTAGACAATAAAGATGGTCCTG	CCAACTCTCTTCCTCTTGTCAT
  		(SEQ ID NO: 4514)	(SEQ ID NO: 4515)	(SEQ ID NO: 4516)
  hCV25598594	A/G	ATATATTGACCGTTCTCCCAT	ATATATTGACCGTTCTCCCAC	GCCACCTCCAACCATATC
  		(SEQ ID NO: 4517)	(SEQ ID NO: 4518)	(SEQ ID NO: 4519)
  hCV25603879	C/T	GAAGTCATTCTGCTCTGC	ATGAAGTCATTCTGCTCTGT	TTTCCATCTCCTAACTCTTTTCTAG
  		(SEQ ID NO: 4520)	(SEQ ID NO: 4521)	(SEQ ID
  				NO: 4522)
  hCV25605897	G/T	AAGGCAGGATGGGAGTG	AAAGGCAGGATGGGAGTT	CGTCAAAGCACTAATGTCATGT
  		(SEQ ID NO: 4523)	(SEQ ID NO: 4524)	(SEQ ID NO: 4525)
  hCV25607193	C/T	GCGCAAAAGGCAAGAC	GCGCAAAAGGCAAGAT	CCTTGGGACACACATTTACAG
  		(SEQ ID NO: 4526)	(SEQ ID NO: 4527)	(SEQ ID NO: 4528)
  hCV25608818	A/G	CTCAATGTCGTATTCACCTTCT	CAATGTCGTATTCACCTTCC	ACTCCAGGATTTTTCAAAGATTAT
  		(SEQ ID NO: 4529)	(SEQ ID NO: 4530)	(SEQ ID
  				NO: 4531)
  hCV25609975	A/C	CTTTGAACCTTTTCACCACA	TTTGAACCTTTTCACCACC	GAGTGAGGAGGGAGAAAGTAAG
  		(SEQ ID NO: 4532)	(SEQ ID NO: 4533)	(SEQ ID
  				NO: 4534)
  hCV25610470	A/G	CACAATCACCACGGTCT	ACAATCACCACGGTCC	CCTTCTGCATCAGCATCTTC
  		(SEQ ID NO: 4535)	(SEQ ID NO: 4536)	(SEQ ID NO: 4537)
  hCV25610774	C/T	GGGTCGGTGCAAGAGG	GGGTCGGTGCAAGAGA	GCACCTTGGTGGGTTTGT
  		(SEQ ID NO: 4538)	(SEQ ID NO: 4539)	(SEQ ID NO: 4540)
  hCV25610819	A/T	GGACGTGGACATGGAGT	GGACGTGGACATGGAGA	CGGCGCTCGTAGGTG
  		(SEQ ID NO: 4541)	(SEQ ID NO: 4542)	(SEQ ID NO: 4543)
  hCV25614016	A/G	AGTGGCCAAGAACACCA	TGGCCAAGAACACCG	GGTATGAGGCAAAGTTCCTG
  		(SEQ ID NO: 4544)	(SEQ ID NO: 4545)	(SEQ ID NO: 4546)
  hCV25617571	C/T	CCAGCAGTATGGACG	TGCCAGCAGTATGGACA	CCATCCAGCCTCAGGAAC
  		(SEQ ID NO: 4547)	(SEQ ID NO: 4548)	(SEQ ID NO: 4549)
  hCV25618493	G/A	GAGGCTGCGTATCC	GGAGGCTGCGTATCT	GTAGCTGTGCAGTGACAGTGT
  		(SEQ ID NO: 4550)	(SEQ ID NO: 4551)	(SEQ ID NO: 4552)
  hCV25623265	A/G	TGGAGGCTGATGGGTA	GGAGGCTGATGGGTG	CGCTTTGCAGCCATAACT
  		(SEQ ID NO: 4553)	(SEQ ID NO: 4554)	(SEQ ID NO: 4555)
  hCV25629396	C/G	AGAACGCCTATGAGGAGTG	AAGAACGCCTATGAGGAGTC	TTGGGTGGCACCATATG
  		(SEQ ID NO: 4556)	(SEQ ID NO: 4557)	(SEQ ID NO: 4558)
  hCV25629476	A/G	ATCTCCTCGGCTGTCTT	ATCTCCTCGGCTGTCTC	AACCTCACCTGGCATGAG
  		(SEQ ID NO: 4559)	(SEQ ID NO: 4560)	(SEQ ID NO: 4561)
  hCV25629492	A/G	CCCACAGCCTGCGAT	CCCACAGCCTGCGAC	CCGCTTGAGGTCCACATA
  		(SEQ ID NO: 4562)	(SEQ ID NO: 4563)	(SEQ ID NO: 4564)
  hCV25629888	C/G	GCACCTTGCTGCTGTCTG	GCACCTTGCTGCTGTCTG	GCCCTGATCACTGCAAAAC
  		(SEQ ID NO: 4565)	(SEQ ID NO: 4566)	(SEQ ID NO: 4567)
  hCV25630686	C/T	AGGTTGTACCTGTAGCACTAAGAC	TAGGTTGTACCTGTAGCACTAAGAT	TGGGCTCCTCAGAGAAAATAT
  		(SEQ ID NO: 4568)	(SEQ ID NO: 4569)	(SEQ ID NO: 4570)
  hCV25631989	C/T	AAGATAAGCCTGTCACTGGTC	AAGATAAGCCTGTCACTGGTT	CAAGCCAGCCTAATAAACATAA
  		(SEQ ID NO: 4571)	(SEQ ID NO: 4572)	(SEQ ID NO: 4573)
  hCV25636622	C/T	TCTGTAGTCAACAGGAGAAGAGAC	TCTGTAGTCAACAGGAGAAGAGAT	GCTGGGTTTTGGTGAAGTT
  		(SEQ ID NO: 4574)	(SEQ ID NO: 4575)	(SEQ ID NO: 4576)
  hCV25637309	A/T	GGCCACTTTGCCTGAATA	GGCCACTTTGCCTGAATT	CGAAATGTTCATTTTTAAAGTCAGA
  		(SEQ ID NO: 4577)	(SEQ ID NO: 4578)	(SEQ ID
  				NO: 4579)
  hCV25640504	C/T	CCAAGATCTTCAGCAACG	ACCAAGATCTTCAGCAACA	TGCAACCTCCACACAATCT
  		(SEQ ID NO: 4580)	(SEQ ID NO: 4581)	(SEQ ID NO: 4582)
  hCV25640504	C/T	CTAAGGTCTTCAGCAATG	CTAAGGTCTTCAGCAATA	TGCAACCTCCACACAATCT
  		(SEQ ID NO: 5415)	(SEQ ID NO: 5416)	(SEQ ID NO: 4582)
  hCV25642473	C/T	CCACATAGATTCCTAAGAACG	ACCACATAGATTCCTAAGAACA	CAAACACCATGGTTTTTCTTT
  		(SEQ ID NO: 4583)	(SEQ ID NO: 4584)	(SEQ ID NO: 4585)
  hCV25643756	C/T	CACTGCCATGCTCG	ACACTGCCATGCTCA	GCTGGCGCAGGAAGTAG
  		(SEQ ID NO: 4586)	(SEQ ID NO: 4587)	(SEQ ID NO: 4588)
  hCV25644901	A/G	CAGACCTGCAGCTTCA	AGACCTGCAGCTTCG	TGTAACCCATCAACTCTGTTTATC
  		(SEQ ID NO: 4589)	(SEQ ID NO: 4590)	(SEQ ID
  				NO: 4591)
  hCV25651076	A/G	GATGCTGGCAAAGAACA	ATGCTGGCAAAGAACG	CAATCATCCACCTTTGTCTGT
  		(SEQ ID NO: 4592)	(SEQ ID NO: 4593)	(SEQ ID NO: 4594)
  hCV25651174	A/G	CGCTGCAGGGTCAT	CGCTGCAGGGTCAC	CCTCCCCGCAGAGAATTA
  		(SEQ ID NO: 4595)	(SEQ ID NO: 4596)	(SEQ ID NO: 4597)
  hCV25652744	C/A	AATGGTCCAGTTCCCTCTC	CAATGGTCCAGTTCCCTCTA	TGAAGTGTGAATGATGCTGATA
  		(SEQ ID NO: 4598)	(SEQ ID NO: 4599)	(SEQ ID NO: 4600)
  hCV25742059	A/G	CTGCCTCTTCTGCATTAGA	TGCCTCTTCTGCATTAGG	CCTTCACTGCCTGTTTCTCT
  		(SEQ ID NO: 4601)	(SEQ ID NO: 4602)	(SEQ ID NO: 4603)
  hCV25745415	G/T	TGACAGAGAATACTGGAAGATATG	CTGACAGAGAATACTGGAAGATATT	CCATCTTGGCCATGTTTAAT
  		(SEQ ID NO: 4604)	(SEQ ID NO: 4605)	(SEQ ID NO: 4606)
  hCV25749177	G/A	CAGTGCTGGAACCTGTAAGTC	CAGTGCTGGAACCTGTAAGTT	TGGAGTCAAAGGTTAAAACTCA
  		(SEQ ID NO: 4607)	(SEQ ID NO: 4608)	(SEQ ID NO: 4609)
  hCV25753038	T/C	GGAGCCACCTATGTTCTCTACT	GAGCCACCTATGTTCTCTACC	TCCCTCTTTGCTCATTCATC
  		(SEQ ID NO: 4610)	(SEQ ID NO: 4611)	(SEQ ID NO: 4612)
  hCV25767229	C/T	GTGTGGCAATGAAGTCCC	AGTGTGGCAATGAAGTCCT	GCAGTGCTCGTTACATGAAAGATC
  		(SEQ ID NO: 4613)	(SEQ ID NO: 4614)	(SEQ ID
  				NO: 4615)
  hCV25767417	A/G	AGCCCCTTGTCTTCCAT	AGCCCCTTGTCTTCCAC	AAAGCAGTTCGACAAAATCTTA
  		(SEQ ID NO: 4616)	(SEQ ID NO: 4617)	(SEQ ID NO: 4618)
  hCV25770061	A/C	CCAAGCGACAGTCATAGTCT	CAAGCGACAGTCATAGTCG	GTGCTGAATGTTTGCTCTGT
  		(SEQ ID NO: 4619)	(SEQ ID NO: 4620)	GTATCTAC
  				(SEQ ID
  				NO: 4621)
  hCV25922320	A/G	CTCGCAGCGGTCAGT	TCGCAGCGGTCAGC	GCTGGCGGGAATTTCT
  		(SEQ ID NO: 4622)	(SEQ ID NO: 4623)	(SEQ ID NO: 4624)
  hCV25922440	C/T	CGAACTCTTCAAGGTGGTTG	CCGAACTCTTCAAGGTGGTTA	CCATGCATGCTTCAGGTAAG
  		(SEQ ID NO: 4625)	(SEQ ID NO: 4626)	(SEQ ID NO: 4627)
  hCV25922816	A/G	TGGCACTCAGGGCAT	TGGCACTCAGGGCAC	CCAAAGAGGACTGACAACTGTA
  		(SEQ ID NO: 4628)	(SEQ ID NO: 4629)	(SEQ ID
  				NO: 4630)
  hCV25924894	A/G	GGGAAGTTCTTTCTTGTATATTCAA	GGGAAGTTCTTTCTTGTATATTCAG	TGCTGTCTTTGCCTCACTAAT
  		(SEQ ID NO: 4631)	(SEQ ID NO: 4632)	(SEQ ID NO: 4633)
  hCV25925481	A/G	AATCAGCATTTTTGTCAAAGA	ATCAGCATTTTTGTCAAAGG	GGCTTGTGACCTCATTGTTT
  		(SEQ ID NO: 4634)	(SEQ ID NO: 4635)	(SEQ ID NO: 4636)
  hCV25925974	G/C	AAAGCAAAGGCACAGAGAG	AAAGCAAAGGCACAGAGAG	TGCCGTGCTGAGTTAATG
  		(SEQ ID NO: 4637)	(SEQ ID NO: 4638)	(SEQ ID NO: 4639)
  hCV25926178	C/G	GCTTTATCAGAGACTCTGAAGC	GCTTTATCAGAGACTCTGAAGG	CCAAGGCCACGGATATC
  		(SEQ ID NO: 4640)	(SEQ ID NO: 4641)	(SEQ ID NO: 4642)
  hCV2592654	A/C	CAGTAAGCTGGAGAGTGGA	AGTAAGCTGGAGAGTGGC	TGGGAGGTGGATAAGGCAGATAAG
  		(SEQ ID NO: 4643)	(SEQ ID NO: 4644)	(SEQ ID
  				NO: 4645)
  hCV2592662	A/G	GTTTGTGGGTTTTGTGGGA	TTTGTGGGTTTTGTGGGG	CAGAGCAGCTTTCAAACTTTCTGAA
  		(SEQ ID NO: 4646)	(SEQ ID NO: 4647)	(SEQ ID
  				NO: 4648)
  hCV25926643	G/A	CCTGGTTAGCTTTACCTTACG	CCCTGGTTAGCTTTACCTTACA	CCCTTGCCATCCACACT
  		(SEQ ID NO: 4649)	(SEQ ID NO: 4650)	(SEQ ID NO: 4651)
  hCV25926771	C/T	GGCCTTGGTCTCGC	TGGCCTTGGTCTCGT	TGCAGATCAGCTTGAAGAACTA
  		(SEQ ID NO: 4652)	(SEQ ID NO: 4653)	(SEQ ID NO: 4654)
  hCV2592715	A/T	CTGACCTTTCCTTTATTAAG	TGACCTTTCCTTTATTAAG	GTGCCGCTGTTTC
  		CATCTATA	CATCTATT	CTCATGT
  		(SEQ ID	(SEQ ID NO: 4656)	(SEQ ID NO: 4657)
  		NO: 4655)
  hCV25927459	G/T	GGCTGTTGCTCCTCTTATG	TGGCTGTTGCTCCTCTTATT	GGACCTGTCAATC
  		(SEQ ID NO: 4658)	(SEQ ID NO: 4659)	TTGGTCATCTAT
  				(SEQ ID
  				NO: 4660)
  hCV2592759	A/C	TCCTCTCAGATAGTGTGAA	CCTCTCAGATAGTGTG	CAACTGAGGCAAATA
  		TACAATA	AATACAATC	CTGTGCTAACT
  		(SEQ ID	(SEQ ID NO: 4662)	(SEQ ID
  		NO: 4661)		NO: 4663)
  hCV25928135	C/T	TTTCACCGTATTAGCCAGG	GTTTCACCGTATTAGCCAGA	CCCATAGTGGCCTCAATAGT
  		(SEQ ID NO: 4664)	(SEQ ID NO: 4665)	(SEQ ID NO: 4666)
  hCV25928538	C/G	TCCACTGTTTTTGAACGC	TCCACTGTTTTTGAACGG	TAATTGCAAGAATATTGAAAGACA
  		(SEQ ID NO: 466/)	(SEQ ID NO: 4668)	(SEQ ID
  				NO: 4669)
  hCV25930271	C/T	GAATCTCATGTTCAGGAAATG	CGAATCTCATGTTCAGGAAATA	GCCATGGCCCATAAAAC
  		(SEQ ID NO: 4670)	(SEQ ID NO: 4671)	(SEQ ID NO: 4672)
  hCV25932224	T/G	AGCCACTAAGCTCAAACTCTTT	GCCACTAAGCTCAAACTCTTG	CCCTAAAACCAAAGACGTATGT
  		(SEQ ID NO: 4673)	(SEQ ID NO: 4674)	(SEQ ID NO: 4675)
  hCV25941408	G/T	CATGGAGTCAACTCTTGAGG	GCATGGAGTCAACTCTTGAGT	GGCTGTGCTTTGTCTGATCT
  		(SEQ ID NO: 4676)	(SEQ ID NO: 4677)	(SEQ ID NO: 4678)
  hCV25942539	G/A	GGATCCGACCGTTGAG	GGATCCGACCGTTGAA	TCATTTTGAACTCATTTTTTCTAGA
  		(SEQ ID NO: 4679)	(SEQ ID NO: 4680)	(SEQ ID
  				NO: 4681)
  hCV25943180	T/C	GGTGGTCTTCCAGTCCTT	GGTGGTCTTCCAGTCCTC	TTGCTCCCTGCGAGTAAG
  		(SEQ ID NO: 4682)	(SEQ ID NO: 4683)	(SEQ ID NO: 4684)
  				AGTGTCAAGGTAATCTGGTTTTT
  hCV25965660	A/G	GGCCTGGTGGAAGTGAT	GGCCTGGTGGAAGTGAC	(SEQ ID
  		(SEQ ID NO: 4685)	(SEQ ID NO: 4686)	NO: 4687)
  hCV25972680	A/G	GCAGGCCTTTCTCAGAAT	GCAGGCCTTTCTCAGAAC	CAGGAAGAGAAGAAGTCACTTGT
  		(SEQ ID NO: 4688)	(SEQ ID NO: 4689)	(SEQ ID
  				NO: 4690)
  hCV25996298	G/T	CAGAGGCTGCTCCGC	ACAGAGGCTGCTCCGA	GGGTTTGTGGGCTCTTC
  		(SEQ ID NO: 4691)	(SEQ ID NO: 4692)	(SEQ ID NO: 4693)
  hCV26000635	C/A	TGCTGGAGCAATTGAGAG	CTGCTGGAGCAATTGAGAT	TCTTCCCCTCGTTTCTTTC
  		(SEQ ID NO: 4694)	(SEQ ID NO: 4695)	(SEQ ID NO: 4696)
  hCV260164	G/T	ACAGGTCACTGGGATTGG	ACAGGTCACTGGGATTGT	CTGGACAGTGTTTGGAAGGTCATA
  		(SEQ ID NO: 4697)	(SEQ ID NO: 4698)	(SEQ ID
  				NO: 4699)
  hCV2604332	G/T	GCAAATCAAGTAAAAGATCTGTTTC	GCAAATCAAGTAAAAGATCTGTTTA	CTGCAGCAGCTAAATGTCA
  		(SEQ ID NO: 4700)	(SEQ ID NO: 4701)	(SEQ ID NO: 4702)
  hCV26294850	C/T	GCCCAAGCGGAAGGTACGACT	GCATACCTTGCCAGTAGCGATGC	GCAGCACGAACTGC
  		TTCCGGCTGAAAGCCG	GGCGGCTGAAAGCCA	(SEQ ID NO: 4705)
  		(SEQ ID NO: 4703)	(SEQ ID NO: 4704)
  hCV2632070	A/G	GACTAAAGTTCTGAGCCAATCAA	ACTAAAGTTCTGAGCCAATCAG	GCCCTTTGTTCCTCGGTTTAGAG
  		(SEQ ID NO: 4706)	(SEQ ID NO: 4707)	(SEQ ID
  				NO: 4708)
  hCV2632498	C/G	CAATTGAGGTCCAGGAGC	CAATTGAGGTCCAGGAGG	TGGTGCAAACAGCTCTTCT
  		(SEQ ID NO: 4709)	(SEQ ID NO: 4710)	(SEQ ID NO: 4711)
  hCV2632544	C/T	ACTGACCCTTCACACATTTAC	GTAACTGACCCTTCACACATTTAT	TGAGCCATCGTGCCTAGCTA
  		(SEQ ID NO: 4712)	(SEQ ID NO: 4713)	(SEQ ID NO: 4714)
  hCV2633049	G/T	CTTCTAGGCTCTGTGGTCC	CTTCTAGGCTCTGTGGTCA	CCACGTGCCCATGAAG
  		(SEQ ID NO: 4715)	(SEQ ID NO: 4716)	(SEQ ID NO: 4717)
  hCV2658421	A/C	CTCTCTTTCAGCATCTTGTAAAT	CTCTCTTTCAGCATCTTGTAAAG	TGCAGAAGAAAGAAACTTTATCAC
  		(SEQ ID NO: 4718)	(SEQ ID NO: 4719)	(SEQ ID
  				NO: 4720)
  hCV26660340	C/G	TGTGTCCAAAGGGACCAC	TGTGTCCAAAGGGACCAG	GACCCCATTTTCCTGGA
  		(SEQ ID NO: 4721)	(SEQ ID NO: 4722)	CCATTAAG
  				(SEQ ID
  				NO: 4723)
  hCV26683367	C/G	CCTATTAAGATGAGAACC	CCTATTAAGATGAGAAC	GGAGGTGGAAGAGCAT
  		TCAACAC	CTCAACAC	TGAAACT
  		(SEQ ID NO: 4724)	(SEQ ID NO: 4725)	(SEQ ID
  				NO: 4726)
  hCV26683368	C/T	TGTAAAATGCCTGTCACGG	GTGTAAAATGCCTGTCACGA	CGATGACATTCTTGGTCT
  		(SEQ ID NO: 4727)	(SEQ ID NO: 4728)	GTACACT
  				(SEQ ID
  				NO: 4729)
  hCV2680532	A/C	GGGCCTCACCTTGGT	GGGCCTCACCTTGGG	GCCTCCCCAGATTGATGTCT
  		(SEQ ID NO: 4730)	(SEQ ID NO: 4731)	(SEQ ID NO: 4732)
  hCV26809148	A/G	CATCATGGTGTTCTTGCCT	ATCATGGTGTTCTTGCCC	CATTATCTGAAATGTTTC
  		(SEQ ID NO: 4733)	(SEQ ID NO: 4734)	ATTGTAGA
  				(SEQ ID
  				NO: 4735)
  hCV26898946	C/T	TGGGTGGCAGTCCC	GTGGGTGGCAGTCCT	GGGGACAGGTATGCATGTCAT
  		(SEQ ID NO: 4736)	(SEQ ID NO: 4737)	(SEQ ID NO: 4738)
  hCV27157435	C/T	GGAACTTAATTGCTTG	GGAACTTAATTGCTTGA	GACACCACCGTCCT
  		ATACTATCAC	TACTATCAT	ACACTG
  		(SEQ ID	(SEQ ID NO: 4740)	(SEQ ID NO: 4741)
  		NO: 4739)
  hCV27157439	A/C	GTAACTAACACTCAGAAGT	GTAACTAACACTCAGAAG	GTTGAGGCTGCAGTGA
  		ACATTTT	TACATTTG	GCTATAAT
  		(SEQ ID NO: 4742)	(SEQ ID NO: 4743)	(SEQ ID
  				NO: 4744)
  hCV2741051	C/T	GCAGCCAGTTTCTCCC	TGCAGCCAGTTTCTCCT	CATGAAATGCTTCCAGGTATT
  		(SEQ ID NO: 4745)	(SEQ ID NO: 4746)	(SEQ ID NO: 4747)
  hCV2741083	C/T	GTTCCAACCAGAAGAGAATG	GGTTCCAACCAGAAGAGAATA	CTTGCCCCCAACAGTTAG
  		(SEQ ID NO: 4748)	(SEQ ID NO: 4749)	(SEQ ID NO: 4750)
  hCV27422538	C/G	GCAATCTCTCCTTCCTCTCC	GCAATCTCTCCTTCCTCTCG	ACACACACACCTCCACAAATACTAA
  		(SEQ ID NO: 4751)	(SEQ ID NO: 4752)	(SEQ ID
  				NO: 4753)
  hCV27457080	C/T	AAATAGGTCGTTCTG	AAATAGGTCGTTCTGAC	CCCACTCCACCATC
  		ACATAAAAG	ATAAAAA	TGTATAG
  		(SEQ ID NO: 4754)	(SEQ ID NO: 4755)	(SEQ ID NO: 4756)
  hCV27462774	A/G	AAGATCATGATTTATCT	AGATCATGATTTATC	GGTGGTCAGCAC
  		TGGTTCCTA	TTGGTTCCTG	ATGACTTCT
  		(SEQ ID NO: 4757)	(SEQ ID NO: 4758)	(SEQ ID NO: 4759)
  hCV27480853	C/T	CCTGTTAGGTGTGTTGCTTTAAC	CCTGTTAGGTGTGTTGCTTTAAT	GCTTACGCCATTTTCTGTCGGTATTT
  		(SEQ ID NO: 4760)	(SEQ ID NO: 4761)	(SEQ ID
  				NO: 4762)
  hCV2762168	C/T	CCCCATGGTTTGTTGTTGC	CCCCATGGTTTGTTGTTGT	CGACTTCAGTGACCACACATAACA
  		(SEQ ID NO: 4763)	(SEQ ID NO: 4764)	(SEQ ID
  				NO: 4765)
  hCV2769554	A/G	TCCGTTGTTCTCAGGGAT	TCCGTTGTTCTCAGGGAC	GGTTCCTGGAGGCATGTC
  		(SEQ ID NO: 4766)	(SEQ ID NO: 4767)	(SEQ ID NO: 4768)
  hCV2781953	G/T	ACATTGCGGTTATTGCTAGTG	ACATTGCGGTTATTGCTAGTT	CACCTGCCTCTCTCAAAGAATAGC
  		(SEQ ID NO: 4769)	(SEQ ID NO: 4770)	(SEQ ID
  				NO: 4771)
  hCV27884601	C/T	GGAATATTTGGGTTTGTTTCACC	GGAATATTTGGGTTTGTTTCACT	CTGGGACTGTCTATTTTCT
  		(SEQ ID NO: 4772)	(SEQ ID NO: 4773)	TTCATTCAACC(SEQ
  				ID NO: 4774)
  hCV27958354	C/T	GCTATGAGGAGAACACAAGA	GCTATGAGGAGAAC	CATTCCCTCTGCCCCT
  		ATATAC (SEQ ID	ACAAGAATATAT	TCTTAGATA
  		NO: 4775)	(SEQ ID NO: 4776)	(SEQ ID NO: 4777)
  hCV27970553	C/T	ACCTAAACTTTGGTATCACCG	CACCTAAACTTTGGTATCACCA	CTCACCCGCTGATATTTGTTTAACCT
  		(SEQ ID NO: 4778)	(SEQ ID NO: 4779)	(SEQ ID
  				NO: 4780)
  hCV28008078	C/T	CTGTCACAAGCAACAGAAAG	TCTGTCACAAGCAACAGAAAA	CGAGGAGGAGATAACTGGATGTGT
  		(SEQ ID NO: 4781)	(SEQ ID NO: 4782)	(SEQ ID
  				NO: 4783)
  hCV28023091	C/T	TTCAGTTCTTTGCAGTA	TTCAGTTCTTTGCAGTA	CATTTGTCTGAGGGTTCACTTGTTGA
  		ATAAACAG	ATAAACAA	(SEQ ID
  		(SEQ ID NO: 4784)	(SEQ ID NO: 4785)	NO: 4786)
  hCV2822674	A/G	GATGCTGGGTGGATGTT	GATGCTGGGTGGATGTC	TGTGGCCCTGAGAATGTAC
  		(SEQ ID NO: 4787)	(SEQ ID NO: 4788)	(SEQ ID NO: 4789)
  hCV282793	C/T	ATCTATTCACAAACACATGAACAAG	ATCTATTCACAAACACATGAACAAA	GAGACACCCAAGCAAACTGAACTTAC
  		(SEQ ID NO: 4790)	(SEQ ID NO: 4791)	(SEQ ID
  				NO: 4792)
  hCV2829795	A/G	GTTTCTCTCCAGTATGAATTCTTT	GTTTCTCTCCAGTATGAATTCTTC	AATTCATTCTGGAGAGAAATCTTAC
  		(SEQ ID NO: 4793)	(SEQ ID NO: 4794)	(SEQ ID
  				NO: 4795)
  hCV28960526	A/T	TGAAGGCACCTGTCATCAT	TGAAGGCACCTGTCATCAA	CTCCTGGTGGGCCTTTTGAAATA
  		(SEQ ID NO: 4796)	(SEQ ID NO: 4797)	(SEQ ID
  				NO: 4798)
  hCV28974083	A/G	TTCACTTCAAGCTTCCAT	TCACTTCAAGCTTCCATA	CCTCCTCTTCTCATCAATC
  		AGTTAT	GTTAC	CCAAATTAGT
  		(SEQ ID NO: 4799)	(SEQ ID NO: 4800)	(SEQ ID
  				NO: 4801)
  hCV28993059	A/G	GAATGAGTAAGGGAAGAGGAAAA	GAATGAGTAAGGGAAGAGGAAAG	GCTGAATTGTCTGACGGAATCT
  		(SEQ ID NO: 4802)	(SEQ ID NO: 4803)	(SEQ ID NO: 4804)
  hCV29011391	A/G	GCTCGGAAAAGCCAAGAAA	GCTCGGAAAAGCCAAGAAG	GATCCAGATTTTGTCAAAGC
  		(SEQ ID NO: 4805)	(SEQ ID NO: 4806)	CACTAGA (SEQ ID
  				NO: 4807)
  hCV29033518	A/T	GCATTATACATGTGCAGTCACATT	GCATTATACATGTGCAGTCACATA	CCACCATGGCTGTGTCTTGT
  		(SEQ ID NO: 4808)	(SEQ ID NO: 4809)	(SEQ ID NO: 4810)
  hCV29135108	A/C	GGAGTGCTTTTATGGCAAAA	GGAGTGCTTTTATGGCAAAC	GCTGATAGTGCAAGTTAG
  		(SEQ ID NO: 4811)	(SEQ ID NO: 4812)	CAACATAGT (SEQ ID
  				NO: 4813)
  hCV29195255	A/C	TCCAGCAATTCCACTTCCA	CCAGCAATTCCACTTCCC	AGAACTAGCAAAGCACCTCTGTAGAA
  		(SEQ ID NO: 4814)	(SEQ ID NO: 4815)	(SEQ ID
  				NO: 4816)
  hCV29195260	A/G	CATTATCTAGTTTCTTTACT	CATTATCTAGTTTCTTTACT	AGCATCTTCTGTGTCC
  		TGTCTTCT	TGTCTTCC	AGCTAAGT
  		(SEQ ID	(SEQ ID NO: 4818)	(SEQ ID
  		NO: 4817)		NO: 4819)
  hCV2932115	C/T	TGGACGTGGGCTTTTTC	TGGACGTGGGCTTTTTT	GCTGCAGCCCTTTTTCTC
  		(SEQ ID NO: 4820)	(SEQ ID NO: 4821)	(SEQ ID NO: 4822)
  hCV29322781	A/G	AGATATCCACTACTCTTCTTCTCAA	AGATATCCACTACTCTTCTTCTCAG	CTTAAGCCAGTCCTGCACAACTAG
  		(SEQ ID NO: 4823)	(SEQ ID NO: 4824)	(SEQ ID
  				NO: 4825)
  hCV29368919	C/T	GCTTCAAGAGGATAAAGTA	GCTTCAAGAGGATAAAG	GATATAACCTGTCACT
  		AAACAGAG	TAAAACAGAA	ACACTGGACTGAA
  		(SEQ ID	(SEQ ID	(SEQ ID
  		NO: 4826)	NO: 4827)	NO: 4828)
  hCV29480044	C/T	GGTGGGCCTTTTGAAATAAAC	TGGTGGGCCTTTTGAAATAAAT	CTTGAAGTGAAGGCACCTGTCAT
  		(SEQ ID NO: 4829)	(SEQ ID NO: 4830)	(SEQ ID
  				NO: 4831)
  hCV2948766	A/G	ACAATAACCCTTCTA	CAATAACCCTTCTA	GTGTTGCTGAAATCAT
  		ATTGCACA	ATTGCACG	GGAGTCTGAT
  		(SEQ ID NO: 4832)	(SEQ ID NO: 4833)	(SEQ ID
  				NO: 4834)
  hCV2960489	A/G	CCCACCATCCACTTCCT	CCCACCATCCACTTCCC	CTCCAGCGTTGGGGATGATG
  		(SEQ ID NO: 4835)	(SEQ ID NO: 4836)	(SEQ ID NO: 4837)
  hCV2966448	A/G	GTTAAACCTTCTTTATCTCCTCCTT	GTTAAACCTTCTTTATCTCCTCCTC	CGCTTCGCCTTGGGATATG
  		(SEQ ID NO: 4838)	(SEQ ID NO: 4839)	(SEQ ID NO: 4840)
  hCV29684678	C/G	CAGCTACACTTCAGTCTACTTAG	CAGCTACACTTCAGTCTACTTAG	GAGAAGGAGACTGGAGACA
  		(SEQ ID NO: 4841)	(SEQ ID NO: 4842)	GATATGAC
  				(SEQ ID
  				NO: 4843)
  hCV29809835	A/C	GTCTCGGAAGCAATGTTCTA	TCTCGGAAGCAATGTTCTC	GCTTCTGCCACCCCTGTAAAT
  		(SEQ ID NO: 4844)	(SEQ ID NO: 4845)	(SEQ ID NO: 4846)
  hCV29819064	C/T	TCGCTTTGAAACACTCTGC	CTCGCTTTGAAACACTCTGT	CTGTGGCTTCAGGCTTTACAGT
  		(SEQ ID NO: 4847)	(SEQ ID NO: 4848)	(SEQ ID NO: 4849)
  hCV2983035	A/G	TTGGACCCTCACATGAAA	TTGGACCCTCACATGAAG	GCCATTTTCCACAATAAATATTT
  		(SEQ ID NO: 4850)	(SEQ ID NO: 4851)	(SEQ ID NO: 4852)
  hCV2983036	C/G	GCTGACTTTTTTGCTCTTTC	GCTGACTTTTTTGCTCTTTG	GCCATTTTCCACAATAAATATTT
  		(SEQ ID NO: 4853)	(SEQ ID NO: 4854)	(SEQ ID NO: 4855)
  hCV2987229	C/T	GGAGGGAGGCAACCAC	GGAGGGAGGCAACCAT	TGCCCGATAAACGTGAGGTAGAA
  		(SEQ ID NO: 4856)	(SEQ ID NO: 4857)	(SEQ ID
  				NO: 4858)
  hCV2987250	C/G	ACTGCTCCAAGATAGAGGTAC	ACTGCTCCAAGATAGAGGTAC	CAGCATTTGTGAGAGGAGCTGTTT
  		(SEQ ID NO: 4859)	(SEQ ID NO: 4860)	(SEQ ID
  				NO: 4861)
  hCV29873524	C/T	TCATCAAACCACTCAAGCTAC	TTTCATCAAACCACTCAAGCTAT	CACTCAAATGGAAGAGTCATTG
  		(SEQ ID NO: 4862)	(SEQ ID NO: 4863)	GTGAAT (SEQ ID
  				NO: 4864)
  hCV2992252	T/C	CCCTGTGATTGGCCAT	CCCTGTGATTGGCCAC	CCTGCTCGCTCTGTCAC
  		(SEQ ID NO: 4865)	(SEQ ID NO: 4866)	(SEQ ID NO: 4867)
  hCV29945430	G/T	GAGCTCATGTGCATTATAAACG	AGAGCTCATGTGCATTATAAACT	CCGCCTACTGACTACCTGTCTA
  		(SEQ ID NO: 4868)	(SEQ ID NO: 4869)	(SEQ ID NO: 4870)
  hCV29952522	A/G	ACTGGAAAGATGACACATCTACA	CTGGAAAGATGACACATCTACG	GGGCTACACCCAAAGGCTAAATC
  		(SEQ ID NO: 4871)	(SEQ ID NO: 4872)	(SEQ ID
  				NO: 4873)
  hCV30136303	C/G	TCACCCCACTCTGCTATAG	TCACCCCACTCTGCTATAG	CAAAGGCTGGGAAGGGTAT
  		(SEQ ID NO: 4874)	(SEQ ID NO: 4875)	GTATATTG
  				(SEQ ID
  				NO: 4876)
  hCV30233466	A/G	GCGCCCGGATGGAAT	GCGCCCGGATGGAAC	ACGCCCACTCCAGTTACTAAACA
  		(SEQ ID NO: 4877)	(SEQ ID NO: 4878)	(SEQ ID
  				NO: 4879)
  hCV3026189	C/T	CTTCTTGCCCTTCAGCTC	CTTCTTGCCCTTCAGCTT	CCCAGTTCTGAGATGTGTATGT
  		(SEQ ID NO: 4880)	(SEQ ID NO: 4881)	(SEQ ID NO: 4882)
  hCV30264691	G/T	TTCTCCTGAAGAATTGTAAGCC	TTTCTCCTGAAGAATTGTAAGCA	GAAGTTAGCCAATCTTGT
  		(SEQ ID NO: 4883)	(SEQ ID NO: 4884)	CATCTTTTCACT (SEQ
  				ID NO: 4885)
  hCV30287627	A/T	AATGCAAAATGCAAACTGTCTAA	CAATGCAAAATGCAAACTGTCTAT	TGGAGTTGTCGTCCTGTGGATAAT
  		(SEQ ID NO: 4886)	(SEQ ID NO: 4887)	(SEQ ID
  				NO: 4888)
  hCV30454150	C/T	TCTAGCAGATTTGTATCAGAACC	TAATCTAGCAGATTTGTATCAGAACT	GCGACCCTCTCTGGTTAAACA
  		(SEQ ID NO: 4889)	(SEQ ID NO: 4890)	(SEQ ID NO: 4891)
  hCV30467730	C/T	CTCTACTGTTTAGAATCG	CTCTACTGTTTAGAAT	CCAGCGGTAATT
  		TTTTCAAC	CGTTTTCAAT	GGAGCAATCTTA
  		(SEQ ID NO: 4892)	(SEQ ID NO: 4893)	(SEQ ID
  				NO: 4894)
  hCV30534667	A/G	AGAACAACTCAAAGGTG	AGAACAACTCAAAGGT	ACATGACCTGTTCTAACTG
  		CAAA	GCAAG	GGAGTTATG
  		(SEQ ID NO: 4895)	(SEQ ID NO: 4896)	(SEQ ID
  				NO: 4897)
  hCV30574599	C/T	CCATGCACACTTTAATGTGTAC	TCCATGCACACTTTAATGTGTAT	CCCAAACACAACAGGC
  		(SEQ ID NO: 4898)	(SEQ ID NO: 4899)	TAGAACAAAT
  				(SEQ ID NO: 4900)
  hCV30586985	A/G	TCGGTGATTGGTACAAGAGTAA	CGGTGATTGGTACAAGAGTAG	GCTGGAATGGTACTCCT
  		(SEQ ID NO: 4901)	(SEQ ID NO: 4902)	GAGTATGT
  				(SEQ ID NO: 4903)
  hCV30606396	C/T	ACATTTGCTCATTCTGTACTCC	CACATTTGCTCATTCTGTACTCT	CAAGAGATCTGGAGGTG
  		(SEQ ID NO: 4904)	(SEQ ID NO: 4905)	GGGATTAT
  				(SEQ ID NO: 4906)
  hCV3068176	A/G	TACCACAGCTTGCTCACAT	TACCACAGCTTGCTCACAC	TTTCCCCCATTTTTGAGTT
  		(SEQ ID NO: 4907)	(SEQ ID NO: 4908)	(SEQ ID NO: 4909)
  hCV30764105	C/G	GGCCCTGAACCTTTCAG	GGCCCTGAACCTTTCAG	CGAATTAGTAAGTTACCAG
  		(SEQ ID NO: 4910)	(SEQ ID NO: 4911)	TGACATCAGC(SEQ
  				ID NO: 4912)
  hCV3086932	G/T	TGTATCGAGAGAGAAAGA	TTGTATCGAGAGAGAA	CTCCACCAAATACCCTCATCTGT
  		TAGTTTG	AGATAGTTTT	TCT
  		(SEQ ID NO: 4913)	(SEQ ID NO: 4914)	(SEQ ID
  				NO: 4915)
  hCV3086948	C/T	CTGGCATATTTTGAAG	CTCTGGCATATTTTGAA	CTCTGGAAAGGGAAAT
  		TATTCTCTG	GTATTCTCTA	GTCACTCTA
  		(SEQ ID NO: 4916)	(SEQ ID NO: 4917)	(SEQ ID
  				NO: 4918)
  hCV3086950	A/G	CTCCTTGCCTCAAATGATTTCT	TCCTTGCCTCAAATGATTTCC	TTCAGTCATACTCATGGTCCA
  		(SEQ ID NO: 4919)	(SEQ ID NO: 4920)	AATCTCATT (SEQ
  				ID NO: 4921)
  hCV3086961	A/C	AAGCATCCAGAGCCTCTTAT	AGCATCCAGAGCCTCTTAG	GCTGTCCACCTGTCACTTT
  		(SEQ ID NO: 4922)	(SEQ ID NO: 4923)	CATAAT (SEQ ID
  				NO: 4924)
  hCV3086983	C/T	GCATAACTAAACTATAGTGT	GCATAACTAAACTATAG	GACGTGGCCAGCCA
  		ACAGACAC	TGTACAGACAT	TCTTC
  		(SEQ ID	(SEQ ID	(SEQ ID NO: 4927)
  		NO: 4925)	NO: 4926)
  hCV3087000	A/G	GAGCATAGAAACAATTT	AGCATAGAAACAATTTT	AGTGTGTGGTTTCAGCA
  		TGTTCCAT	GTTCCAC	GTACTAGATT
  		(SEQ ID NO: 4928)	(SEQ ID NO: 4929)	(SEQ ID
  				NO: 4930)
  hCV3087003	C/G	CCTGGGCAAGATGGTAAAAC	CCTGGGCAAGATGGTAAAAG	CTGGGCTCAGGCAATCCTA
  		(SEQ ID NO: 4931)	(SEQ ID NO: 4932)	(SEQ ID NO: 4933)
  hCV3087008	A/C	CAGAGTCCTTCAGTAA	CAGAGTCCTTCAGTA	CCACCTTCTTTCAACC
  		ACTTCTTT	AACTTCTTG	CAAATTTTCTC
  		(SEQ ID NO: 4934)	(SEQ ID NO: 4935)	(SEQ ID
  				NO: 4936)
  hCV3087015	C/G	ACAGCTTTTACTTACCTTT	ACAGCTTTTACTTACCTTT	AGCTGAGTGGGAGAG
  		GATAGAG	GATAGAG	AAGAATACAC
  		(SEQ ID NO: 4937)	(SEQ ID NO: 4938)	(SEQ ID
  				NO: 4939)
  hCV3087016	A/C	AGCACTCCATAACTTTACCCT	GCACTCCATAACTTTACCCG	GACTACACACAAGA
  		(SEQ ID NO: 4940)	(SEQ ID NO: 4941)	TCAACTAA
  				TAGAAATACTGC
  				(SEQ ID NO: 4942)
  hCV3111721	C/T	ACCGTTGTCCTCCC	GACCGTTGTCCTCCT	GCCTCTAGCACGATGGATAG
  		(SEQ ID NO: 4943)	(SEQ ID NO: 4944)	(SEQ ID NO: 4945)
  hCV3111822	C/T	AAACCTTCCTACACAGAACTTC	AAACCTTCCTACACAGAACTTT	CTGGTGGTGGTGAGAAGAACAT
  		(SEQ ID NO: 4946)	(SEQ ID NO: 4947)	(SEQ ID
  				NO: 4948)
  hCV31145250	A/C	CTGAGCCACCTTATCTGTTAAAA	TGAGCCACCTTATCTGTTAAAC	CACAGGGTTGTTAACCTTGGTTTAG
  		(SEQ ID NO: 4949)	(SEQ ID NO: 4950)	(SEQ ID
  				NO: 4951)
  hCV31161091	A/G	ACACCTGCTGACTATCCAAT	CACCTGCTGACTATCCAAC	CATCGTGATCCTGCCAAGTAGAGA
  		(SEQ ID NO: 4952)	(SEQ ID NO: 4953)	(SEQ ID
  				NO: 4954)
  hCV31237961	A/C	GGCGAAGACAAAATTATATTTCAACT	GGCGAAGACAAAATTATATTTCAACG	CCAGGAAGCTCAGGCAAATTTGA
  		(SEQ ID	(SEQ ID NO: 4956)	(SEQ ID
  		NO: 4955)		NO: 4957)
  hCV3135085	G/T	CTGGAAATGGTTATGGGC	TACTGGAAATGGTTATGGGA	TTTATAGGCGTGAAACTAATTCTC
  		(SEQ ID NO: 4958)	(SEQ ID NO: 4959)	(SEQ ID
  				NO: 4960)
  hCV31356445	G/T	GCCTGTGGTTGTCTTCCC	GCCTGTGGTTGTCTTCCA	ACTTCCTCAGGTCTGCTGTGT
  		(SEQ ID NO: 4961)	(SEQ ID NO: 4962)	(SEQ ID NO: 4963)
  hCV31466171	A/G	CTCCAATCCCACATTTCCA	TCCAATCCCACATTTCCG	CCATGACTCTTCAGAACCTGTTTGT
  		(SEQ ID NO: 4964)	(SEQ ID NO: 4965)	(SEQ ID
  				NO: 4966)
  hCV3152623	A/C	CTGCAGAAACGATCAGTGT	TGCAGAAACGATCAGTGG	TGCTTCTGTCATTCTTTCTGAT
  		(SEQ ID NO: 4967)	(SEQ ID NO: 4968)	(SEQ ID NO: 4969)
  hCV31528409	A/G	TGCCTGGACTGTGTTCTT	TGCCTGGACTGTGTTCTC	GAGGCAGAGGTTTCAGTGAGTAGA
  		(SEQ ID NO: 4970)	(SEQ ID NO: 4971)	(SEQ ID
  				NO: 4972)
  hCV3168675	A/G	TCTCCCACTGTGTTCCTA	CTCCCACTGTGTTCCTG	TGCCAGGGATTGGTTGCTTAATAC
  		(SEQ ID NO: 4973)	(SEQ ID NO: 4974)	(SEQ ID
  				NO: 4975)
  hCV3170445	C/T	GCTGCAAAAATGAACAACAC	GCTGCAAAAATGAACAACAT	GAATGCATAGCTGATCTCAAGA
  		(SEQ ID NO: 4976)	(SEQ ID NO: 4977)	(SEQ ID NO: 4978)
  hCV3170459	C/T	GACTGTCCTGATTGGAATCC	TGACTGTCCTGATTGGAATCT	GGCATTTTGGTATCATTTTGTTA
  		(SEQ ID NO: 4979)	(SEQ ID NO: 4980)	(SEQ ID
  				NO: 4981)
  hCV3179059	G/T	CATCCTCGTGGGAAGTG	CATCCTCGTGGGAAGTT	CCAACCTCTGCTCTCTGATAAT
  		(SEQ ID NO: 4982)	(SEQ ID NO: 4983)	(SEQ ID NO: 4984)
  hCV3180404	A/G	CAGCAGAGCAGCCTTAA	CAGCAGAGCAGCCTTAG	TGATGCTGGAAGCACTTCT
  		(SEQ ID NO: 4985)	(SEQ ID NO: 4986)	(SEQ ID NO: 4987)
  hCV3181997	A/G	TGGATCCTGACTTTGTGAAAT	TGGATCCTGACTTTGTGAAAC	GGAATCTGAAGGAGACATTTTTAC
  		(SEQ ID NO: 4988)	(SEQ ID NO: 4989)	(SEQ ID
  				NO: 4990)
  hCV3187716	A/C	CCTTCAATTCTGAAAAGTAGCTAAT	CCTTCAATTCTGAAAAGTAGCTAAG	TTTGAGGTTGAGTGACATGTTC
  		(SEQ ID NO: 4991)	(SEQ ID NO: 4992)	(SEQ ID NO: 4993)
  hCV31954792	A/C	CCGGAGGCTAGATTATTACCT	CGGAGGCTAGATTATTACCG	ATCCCATTCCCTCCCTTCACATAA
  		(SEQ ID NO: 4994)	(SEQ ID NO: 4995)	(SEQ ID
  				NO: 4996)
  hCV3201490	A/G	GCAGTCCTGCCGTACT	GCAGTCCTGCCGTACC	ACTGCTCAACTACCTGGTG
  		(SEQ ID NO: 4997)	(SEQ ID NO: 4998)	GATAAG
  				(SEQ ID
  				NO: 4999)
  hCV32055474	C/G	GAACAGTTCAGATTTACAAGTGC	AGAACAGTTCAGATTTACAAGTGG	CCACTGTTAACATTTGT
  		(SEQ ID N0:5000)	(SEQ ID NO: 5001)	TGTATGGTCAGT
  				(SEQ ID
  				NO: 5002)
  hCV32055477	A/G	GAGTGCTAACAGAGTAATTACCAA	GAGTGCTAACAGAGTAATTACCAG	AAGGTCTCACCTGGTATG
  		(SEQ ID NO: 5003)	(SEQ ID NO: 5004)	CTGTATTTT
  				(SEQ ID
  				NO: 5005)
  hCV32055527	A/C	ACACCCCAACGTCATCA	ACACCCCAACGTCATCC	AAGCCTTGGAAAGCGAAACTGT
  		(SEQ ID NO: 5006)	(SEQ ID NO: 5007)	(SEQ ID
  				NO: 5008)
  hCV32055581	A/G	GTGAGACAGCAAACACTATACA	TGAGACAGCAAACACTATACG	TTCCCGAAGAGCTGGAATTACAGT
  		(SEQ ID NO: 5009)	(SEQ ID NO: 5010)	(SEQ ID
  				NO: 5011)
  hCV32055595	C/T	ACCATCTACTATGAGCCTCC	AAACCATCTACTATGAGCCTCT	GTCTGTTGCCCATGGATGATTACA
  		(SEQ ID NO: 5012)	(SEQ ID NO: 5013)	(SEQ ID
  				NO: 5014)
  hCV32055596	A/G	GAAACTAGTTCTGTCTTCTAGCAT	GAAACTAGTTCTGTCTTCTAGCAC	GGGTCACAGACTTAGCCAGTGATA
  		(SEQ ID NO: 5015)	(SEQ ID NO: 5016)	(SEQ ID
  				NO: 5017)
  hCV32055625	C/T	CTTCAGACAAGCTGTCCTG	ATCTTCAGACAAGCTGTCCTA	GAAACCTAATTGGCCCAGGTCATC
  		(SEQ ID NO: 5018)	(SEQ ID NO: 5019)	(SEQ ID
  				NO: 5020)
  hCV32055654	A/G	TGATGCACAAGAGTGTTTACTTT	TGATGCACAAGAGTGTTTACTTC	GAGCTTGGATTAGGCAAT
  		(SEQ ID NO: 5021)	(SEQ ID NO: 5022)	GGTTTCT
  				(SEQ ID
  				NO: 5023)
  hCV3215409	A/G	GTGGCTCATTACCAATCTCTT	GTGGCTCATTACCAATCTCTC	GGGCTCCATCAACATCAC
  		(SEQ ID NO: 5024)	(SEQ ID NO: 5025)	(SEQ ID NO: 5026)
  hCV3219460	G/T	GCAGGCCCCAGATGAG	GCAGGCCCCAGATGAT	CCATCCCACCCAGTCAA
  		(SEQ ID NO: 5027)	(SEQ ID NO: 5028)	(SEQ ID NO: 5029)
  hCV323070	A/G	GCCCAGAAAGATGAGTTCA	GCCCAGAAAGATGAGTTCG	TGTCCCTTTTTCAGAGAC
  		(SEQ ID NO: 5030)	(SEQ ID NO: 5031)	ATAGAT
  				(SEQ ID
  				NO: 5032)
  hCV323071	A/G	AAACCAGGATATCAGAACATTTTA	ACCAGGATATCAGAACATTTTG	GGTCTTAGGAATTATCTG
  		(SEQ ID NO: 5033)	(SEQ ID NO: 5034)	ACATCTT
  				(SEQ ID
  				NO: 5035)
  hCV3242919	A/C	GTGAGTTTTCGTCCCACT	TGAGTTTTCGTCCCACG	AAGTGGCCTTTTCTAAGGG
  		(SEQ ID NO: 5036)	(SEQ ID NO: 5037)	GTAGAA
  				(SEQ ID
  hCV3242952	A/G	GCTATGTGGTTTGAAATTGTTCT	GCTATGTGGTTTGAAATTGTTCC	NO: 5038)
  		(SEQ ID NO: 5039)	(SEQ ID NO: 5040)
  hCV3259235	A/G	TCCTCTCCTTGTATCTTCACAT	TCCTCTCCTTGTATCTTCACAC	GGAGCACTGGGTCCTAGATGT
  		(SEQ ID NO: 5042)	(SEQ ID NO: 5043)	(SEQ ID NO: 5041)
  				NO: 5044)
  hCV3275199	A/G	CCATGCAACCAAACCAT	CCATGCAACCAAACCAC	CCTCTCATCCCTCTCATCTTT
  		(SEQ ID NO: 5045)	(SEQ ID NO: 5046)	(SEQ ID NO: 5047)
  hCV334752	C/T	CTGTTCCAATATCTCTTTCCCC	TCTGTTCCAATATCTCTTTCCCT	GCAAACCATAGCACGCTTATACA
  		(SEQ ID NO: 5048)	(SEQ ID NO: 5049)	(SEQ ID
  				NO: 5050)
  hCV341736	C/T	GTCTGGTGACATAAG	GTCTGGTGACATAAGGTA	AGGTGAATTACATAGGACCC
  		GTATTAAATTAAATC	TTAAATTAAATT	TTTGTGT
  		NO:(SEQ ID 5051)	(SEQ ID NO: 5052)	(SEQ ID NO: 5053)
  hCV342590	C/T	AGACAAATTCTCTCATGTCCAC	AGACAAATTCTCTCATGTCCAT	TGTTTTTCCAGGAAAAAG
  		(SEQ ID NO: 5054)	(SEQ ID NO: 5055)	ATATTC
  				(SEQ ID
  				NO: 5056)
  hCV361088	A/G	CGACTTTCTAGAGGAAATTTAGGT	CGACTTTCTAGAGGAAATTTAGGC	CCCAGCAGTCCCGTTGCTTT
  		(SEQ ID NO: 5057)	(SEQ ID NO: 5058)	(SEQ ID NO: 5059)
  hCV370782	C/T	TCTACCCAGGTACTTATCATCC	TTTCTACCCAGGTACTTATCATCT	GGATTCACTGTGAAAGAA
  		(SEQ ID NO: 5060)	(SEQ ID NO: 5061)	CAGTAT
  				(SEQ ID
  				NO: 5062)
  hCV435368	T/C	GAGGTCTTGAAATACAGGGATT	GAGGTCTTGAAATACAGGGATC	TCTTGAGAGGTGTGATCA
  		(SEQ ID NO: 5063)	(SEQ ID NO: 5064)	TAACTT
  				(SEQ ID
  				NO: 5065)
  hCV461035	C/T	TGTTTCCCTTATGACAACACG	CTGTTTCCCTTATGACAACACA	AGGGTCGGTCAAACTCATG
  		(SEQ ID NO: 5066)	(SEQ ID NO: 5067)	CTATAT
  				(SEQ ID
  				NO: 5068)
  hCV472000	A/G	AAGAATTCACACCCAGGTTTATT	AGAATTCACACCCAGGTTTATC	CAACTCCTGAGTTCAAGCA
  		(SEQ ID NO: 5069)	(SEQ ID NO: 5070)	GTCTG
  				(SEQ ID
  				NO: 5071)
  hCV487868	C/T	GCCACAATTTGGAGTTACAGG	GCCACAATTTGGAGTTACAGA	CCAATCCAGCCCTCTTGTG
  		(SEQ ID NO: 5072)	(SEQ ID NO: 5073)	TTTG
  				(SEQ ID
  				NO: 5074)
  hCV491676	T/C	GAATTGCAAGTGCTTGTTTTAT	GAATTGCAAGTGCTTGTTTTAC	CCGATTCCCCAGTAACAAC
  		(SEQ ID NO: 5075)	(SEQ ID NO: 5076)	(SEQ ID NO: 5077)
  hCV529178	C/T	TGGGTTGGTGGGCAG	TGGGTTGGTGGGCAA	GTGGCAGCCAATCTGAGTACT
  		(SEQ ID NO: 5078)	(SEQ ID NO: 5079)	(SEQ ID NO: 5080)
  hCV529706	C/G	GCGAGGACGAAGGGG	GCGAGGACGAAGGGG	GGAGGATGAATGGACAGACAA
  		(SEQ ID NO: 5081)	(SEQ ID NO: 5082)	(SEQ ID NO: 5083)
  hCV529710	C/G	CCGACCCGAACTAAAGG	CCGACCCGAACTAAAGG	CGCGTTCCCCATGTC
  		(SEQ ID NO: 5084)	(SEQ ID NO: 5085)	(SEQ ID NO: 5086)
  hCV537525	A/C	TCATAGATCCCTACTTGTGCTAA	TCATAGATCCCTACTTGTGCTAC	CGCACTGTTCCCTTATCGAGATT
  		(SEQ ID NO: 5087)	(SEQ ID NO: 5088)	(SEQ ID
  				NO: 5089)
  hCV5478	C/T	CGGCTTTCTGGTGGG	ACGGCTTTCTGGTGGA	GGCTCCGAGGACGAGA
  		(SEQ ID NO: 5090)	(SEQ ID NO: 5091)	(SEQ ID NO: 5092)
  hCV549926	C/T	ACCATGGTCACCCTGG	CACCATGGTCACCCTGA	GGACTGAAAGCAATGTGAGAG
  		(SEQ ID NO: 5093)	(SEQ ID NO: 5094)	(SEQ ID NO: 5095)
  hCV561574	A/G	GCCATTTATGTAGCCAAACTGA	GCCATTTATGTAGCCAAACTGG	GCAGGTTATAAAGTGTGA
  		(SEQ ID NO: 5096)	(SEQ ID NO: 5097)	GAGATCTGAGTA (SEQ
  				ID NO: 5098)
  hCV594695	A/T	ATATCGTGGGTGAGTTCATTTA	TCGTGGGTGAGTTCATTTT	GGGTGCTGCTGATGAAATAC
  		(SEQ ID NO: 5099)	(SEQ ID NO: 5100)	(SEQ ID NO: 5101)
  hCV597227	C/T	TTTCTGCAAACTAATTGACAGAAC	CTTTCTGCAAACTAATTGACAGAAT	GTCAAGTCCTTTCGGAAATG
  		(SEQ ID NO: 5102)	(SEQ ID NO: 5103)	AGACA
  				(SEQ ID
  				NO: 5104)
  hCV598677	G/T	CCAAGCTGAAAGGCAAG	CCAAGCTGAAAGGCAAT	CAGCCAGGGTGGAGAGT
  		(SEQ ID NO: 5105)	(SEQ ID NO: 5106)	(SEQ ID NO: 5107)
  hCV601946	A/G	CTCCATTCTCTTACCCCTCTTAT	TCCATTCTCTTACCCCTCTTAC	TTGGGGATGGACTCAAG
  		(SEQ ID NO: 5108)	(SEQ ID NO: 5109)	ATGTGT
  				(SEQ ID
  				NO: 5110)
  hCV601961	A/G	CCATTAATTATGAGTGCTCTT	CCATTAATTATGAGTGCTCT	CCAACCACTCTGGTAGAC
  		ACCTAAA (SEQ ID	TACCTAAG (SEQ ID	GTGTAA
  				(SEQ ID
  		NO: 5111)	NO: 5112)	NO: 5113)
  hCV601962	A/G	AGCATAGAGGACTTCCTGTTT	AGCATAGAGGACTTCCTGTTC	GTGCTGGGATTACAGGCA
  		(SEQ ID NO: 5114)	(SEQ ID NO: 5115)	AGAG
  				(SEQ ID
  				NO: 5116)
  hCV610861	C/T	TGGTGCTTGTTAAAATTTGCTG	GTGGTGCTTGTTAAAATTTGCTA	CTAAATCAGGTTTAT
  		(SEQ ID NO: 5117)	(SEQ ID NO: 5118)	TTGCCATGGAAGAGA (SEQ
  				ID NO: 5119)
  hCV621313	C/T	TCCATGTGTCTGCTACCTC	TCCATGTGTCTGCTACCTT	CTCTTTCCCGGCATACCTGAAT
  		(SEQ ID NO: 5120)	(SEQ ID NO: 5121)	(SEQ ID NO: 5122)
  hCV7425232	C/T	TCAAAATTATTTCTTGCTACAGG	GTCAAAATTATTTCTTGCTACAGA	TCCTCCAGCCTCTCATTC
  		(SEQ ID NO: 5123)	(SEQ ID NO: 5124)	(SEQ ID NO: 5125)
  hCV7435390	A/G	GTGGCCAGGGAAACAT	GTGGCCAGGGAAACAC	CCATGGCGAAGCAAATAT
  		(SEQ ID NO: 5126)	(SEQ ID NO: 5127)	(SEQ ID NO: 5128)
  hCV7441704	A/G	CCAACCGAGATCAGATTGA	CAACCGAGATCAGATTGG	TGATGCTGATTGTGGATGATA
  		(SEQ ID NO: 5129)	(SEQ ID NO: 5130)	(SEQ ID NO: 5131)
  hCV7442005	A/G	ACTTAACACTACTGAAC	ACTTAACACTACTGAACTGT	CACACACGCCCCTAAAC
  		TGTACATTT	ACATTC	AATAGAT
  		(SEQ ID NO: 5132)	(SEQ ID NO: 5133)	(SEQ ID
  				NO: 5134)
  hCV7442014	C/A	AGCAAAACCTTACAAATGTGAC	AGCAAAACCTTACAAATGTGAA	TTACCACATTCATTGCATTTG
  		(SEQ ID NO: 5135)	(SEQ ID NO: 5136)	(SEQ ID NO: 5137)
  hCV7443062	T/C	GGAGCAGGATGGTGAT	GGAGCAGGATGGTGAC	GGAAATATCTCGTTCTTGTTCTCT
  		(SEQ ID NO: 5138)	(SEQ ID NO: 5139)	(SEQ ID
  				NO: 5140)
  hCV7451269	A/G	CTTCCACTCAGCTTCTTGT	TTCCACTCAGCTTCTTGC	GTAACGGGAGCCCCTACAC
  		(SEQ ID NO: 5141)	(SEQ ID NO: 5142)	(SEQ ID NO: 5143)
  hCV7475492	C/T	CCAGACTTACCGATGTAGAC	CCAGACTTACCGATGTAGAT	GAGGGCCGCAGAGGT
  		(SEQ ID NO: 5144)	(SEQ ID NO: 5145)	(SEQ ID NO: 5146)
  hCV7480314	C/T	GCATAGCCAAGGACTCCAC	GCATAGCCAAGGACTCCAT	AGGTGACAGGAGTCCCTACAAC
  		(SEQ ID NO: 5147)	(SEQ ID NO: 5148)	(SEQ ID
  				NO: 5149)
  hCV7490135	C/T	GCAGTCCTGAACAAAGTAGATG	CGCAGTCCTGAACAAAGTAGATA	CGTGCATGTTTTGAAAAATGTA
  		(SEQ ID NO: 5150)	(SEQ ID NO: 5151)	(SEQ ID NO: 5152)
  hCV7494810	C/G	CCCGAGCGGACAGTG	CCCGAGCGGACAGTG	CAACTGCTGGCAGAATCTTC
  		(SEQ ID NO: 5153)	(SEQ ID NO: 5154)	(SEQ ID NO: 5155)
  hCV7499212	C/T	GTGATGGTAGACACCTGGG	TGTGATGGTAGACACCTGGA	GGCTGCACGGACTCTTC
  		(SEQ ID NO: 5156)	(SEQ ID NO: 5157)	(SEQ ID NO: 5158)
  hCV7501549	C/T	TCAGTTGTTGTGGGCTG	CTCAGTTGTTGTGGGCTA	GCCCACCTGCAAGGAATAGAG
  		(SEQ ID NO: 5159)	(SEQ ID NO: 5160)	(SEQ ID NO: 5161)
  hCV7504854	A/G	TCTGGTGCGTAGAATTCCT	TGGTGCGTAGAATTCCC	ACAGCAGCAACGATCTCA
  		(SEQ ID NO: 5162)	(SEQ ID NO: 5163)	(SEQ ID NO: 5164)
  hCV7514870	A/C	GAGCAGCAGGTTTGAGGT	GCAGCAGGTTTGAGGG	ACACCACCTGAACGTCTCTT
  		(SEQ ID NO: 5165)	(SEQ ID NO: 5166)	(SEQ ID NO: 5167)
  hCV7514879	A/G	GGCTGAACCCCGTCCT	GCTGAACCCCGTCCC	CTTTTTCCTGCATCCTGTCT
  		(SEQ ID NO: 5168)	(SEQ ID NO: 5169)	(SEQ ID NO: b1/0)
  hCV7537517	C/G	CAGACCCCATTTTACAATAAAGC	TCAGACCCCATTTTACAATAAAGG	ACCTGGATTCTAT
  		(SEQ ID NO: 5171)	(SEQ ID NO: 5172)	TTTCATCCCATTACATAAGAG
  				(SEQ ID NO: 5173)
  hCV7577801	C/T	CTTTGCTGCTCTGCC	CCTTTGCTGCTCTGCT	GGTCTCTGGTATTAAGTGG
  		(SEQ ID NO: 5174)	(SEQ ID NO: 5175)	AAACA
  				(SEQ ID
  				NO: 5176)
  hCV7618856	C/T	GGCTCCCAATGTTAGTGC	TGGCTCCCAATGTTAGTGT	GGATTGGTTTGCATTTATTT
  		(SEQ ID NO: 5177)	(SEQ ID NO: 5178)	TAGTA
  				(SEQ ID
  				NO: 5179)
  hCV783138	A/G	CATGCCACCCACTACCA	ATGCCACCCACTACCG	GAGCTTTTGCAGCCACTC
  		(SEQ ID NO: 5180)	(SEQ ID NO: 5181)	(SEQ ID NO: 5182)
  hCV783184	G/T	TGCGAGTCAAATCTCAAGAC	TGCGAGTCAAATCTCAAGAA	CCTATTCCCGGCACTTCT
  		(SEQ ID NO: 5183)	(SEQ ID NO: 5184)	(SEQ ID NO: 5185)
  hCV7841642	A/G	ACCAGCTCCAGGGTGTT	ACCAGCTCCAGGGTGTC	TGAAGTTTTGGAATGAGAC
  		(SEQ ID NO: 5186)	(SEQ ID NO: 5187)	TGAT
  				(SEQ ID
  				NO: 5188)
  hCV7900503	C/T	CGTCTCCAGGAAAATCATAAC	CGTCTCCAGGAAAATCATAAT	TGAGTTATTGCTACTTCAG
  		(SEQ ID NO: 5189)	(SEQ ID NO: 5190)	AATCAT
  				(SEQ ID
  				NO: 5191)
  hCV7910239	A/G	CACTTTGTAACCTAAGAGATGCT	ACTTTGTAACCTAAGAGATGCC	GAGAACTCTAGTGAGTCTG
  		(SEQ ID NO: 5192)	(SEQ ID NO: 5193)	TCCTTCAA
  				(SEQ ID
  				NO: 5194)
  hCV795441	C/G	TGTGGGCCAGGACG	CTGTGGGCCAGGACC	ACCCACCAGGACCTAAAAG
  		(SEQ ID NO: 5195)	(SEQ ID NO: 5196)	(SEQ ID NO: 5197)
  hCV795442	A/G	CCATTCAATGCAATACGTCA	CATTCAATGCAATACGTCG	CCTCTCCTTCCAGAACCAGT
  		(SEQ ID NO: 5198)	(SEQ ID NO: 5199)	(SEQ ID NO: 5200)
  hCV8072964	A/T	CCTGATATCCTTGTTCATCAT	CCTGATATCCTTGTTCATCAA	TGTTACGGCTGCTATAATGTGT
  		(SEQ ID NO: 5201)	(SEQ ID NO: 5202)	(SEQ ID NO: 5203)
  hCV8157049	C/T	AGAAGCTGTGTGTCTGGC	CAGAAGCTGTGTGTCTGGT	TGGGTAGATGTGGAATCAATAC
  		(SEQ ID NO: 5204)	(SEQ ID NO: 5205)	(SEQ ID NO: 5206)
  hCV818008	C/T	GCGAGGTGAGCCCG	AGCGAGGTGAGCCCA	GGGATTATCCCAGGAAAGAC
  		(SEQ ID NO: 5207)	(SEQ ID NO: 5208)	(SEQ ID NO: 5209)
  hCV8369472	A/G	CTTGACTGAAAAGTCTGGTCA	TTGACTGAAAAGTCTGGTCG	GTTTCATGGAGGGCTCAGAACT
  		(SEQ ID NO: 5210)	(SEQ ID NO: 5211)	(SEQ ID
  				NO: 5212)
  hCV8379452	C/T	TGATTGCTCTCCTTTGCC	GTGATTGCTCTCCTTTGCT	CCACCTGTATCTGCCATTTCTCT
  		(SEQ ID NO: 5213)	(SEQ ID NO: 5214)	(SEQ ID
  				NO: 5215)
  hCV8420416	C/T	CATTATGAGGGTTACAA	ACATTATGAGGGTTAC	GGGAAACTCACTTC
  		GAATACTCC	AAGAATACTCT	TGTAGGTAA
  		(SEQ ID NO: 5216)	(SEQ ID NO: 5217)	(SEQ ID
  				NO: 5218)
  hCV8687255	C/T	CCTGCTTCAGAGGCTGAC	CCTGCTTCAGAGGCTGAT	CCTCTTCTGGCCTTT
  		(SEQ ID NO: 5219)	(SEQ ID NO: 5220)	CCATACAAT
  				(SEQ ID
  				NO: 5221)
  hCV8696050	A/G	GTGCCACGGTCAGGT	TGCCACGGTCAGGC	GTGCAACCACCACTTG
  		(SEQ ID NO: 5222)	(SEQ ID NO: 5223)	TCTTTAGTT
  				(SEQ ID
  				NO: 5224)
  hCV8696079	G/T	CAACCTCAGTGGAAAGATGC	TCAACCTCAGTGGAAAGATGA	GCCCATGTGCAAAGGTCTCA
  		(SEQ ID NO: 5225)	(SEQ ID NO: 5226)	(SEQ ID NO: 5227)
  hCV8705506	C/G	CCACTTCGGGTTCCTC	CCACTTCGGGTTCCTG	CCCTGGCTTCAACATGA
  		(SEQ ID NO: 5228)	(SEQ ID NO: 5229)	(SEQ ID NO: 5230)
  hCV8708473	A/G	GCAACAGGACACCTGAA	GCAACAGGACACCTGAG	GAGTGACAGGAGGCTGCTTA
  		(SEQ ID NO: 5231)	(SEQ ID NO: 5232)	(SEQ ID NO: 5233)
  hCV8709053	A/G	GCCCAGATACCCCAAAA	GCCCAGATACCCCAAAG	GCCCAGCCTGCGTAGA
  		(SEQ ID NO: 5234)	(SEQ ID NO: 5235)	(SEQ ID NO: 5236)
  hCV8718197	A/G	CCTCTGAGGCCTGAGAAA	CCTCTGAGGCCTGAGAAG	GTCCTGATTCCTCATTTCTTTC
  		(SEQ ID NO: 5237)	(SEQ ID NO: 5238)	(SEQ ID NO: 5239)
  hCV8722613	C/T	CCTGGGGCAGGTACAG	CCTGGGGCAGGTACAA	CCATCCACTGCTTGAAAAG
  		(SEQ ID NO: 5240)	(SEQ ID NO: 5241)	(SEQ ID NO: 5242)
  hCV8726337	A/G	CACATTCACGGTCACCTT	CACATTCACGGTCACCTC	CATTGCCCGAGCTCAA
  		(SEQ ID NO: 5243)	(SEQ ID NO: 5244)	(SEQ ID NO: 5245)
  hCV8737990	C/T	GTCCTTGCAAGTATCCG	GGTCCTTGCAAGTATCCA	GCACTACAGCTGAGTCCTTTTC
  		(SEQ ID NO: 5246)	(SEQ ID NO: 5247)	(SEQ ID NO: 5248)
  hCV8784787	A/C	ACTTCTGGGGCTTAGGAA	ACTTCTGGGGCTTAGGAC	TTCACCGGGAACTCTTGT
  		(SEQ ID NO: 5249)	(SEQ ID NO: 5250)	(SEQ ID NO: 5251)
  hCV8785824	A/C	ATTTACAGAAGCTGCAAGAACT	ACAGAAGCTGCAAGAACG	CATTTTCTGTTTCTGGAT
  		(SEQ ID NO: 5252)	(SEQ ID NO: 5253)	CTGGCAGTAG (SEQ ID
  				NO: 5254)
  hCV8785827	A/G	AGCAAGAACCAGTGATAGGTT	GCAAGAACCAGTGATAGGTC	CCTGTTGGCATGCTTGATGATG
  		(SEQ ID NO: 5255)	(SEQ ID NO: 5256)	(SEQ ID NO: 5257)
  hCV8804621	A/G	AGGTTTCTTGGAGGAAGAGAT	AGGTTTCTTGGAGGAAGAGAC	GCACTGCACCCAGTGAG
  		(SEQ ID NO: 5258)	(SEQ ID NO: 5259)	(SEQ ID NO: 5260)
  hCV8804684	A/T	TGTGTATATCCACGGCATTAT	TGTGTATATCCACGGCATTAA	TGCCCTCACCCAATATTC
  		(SEQ ID NO: 5261)	(SEQ ID NO: 5262)	(SEQ ID NO: 5263)
  hCV881283	C/G	TCAGACACACAGGACACATG	TTCAGACACACAGGACACATC	CCCTTCTGCTCCCAGAAC
  		(SEQ ID NO: 5264)	(SEQ ID NO: 5265)	(SEQ ID NO: 5266)
  hCV8823713	C/T	CCGTTATAATCGAAGGGACAC	TCCGTTATAATCGAAGGGACAT	GCTTCTCCACTTTCTCACATCAGT
  		(SEQ ID NO: 5267)	(SEQ ID NO: 5268)	(SEQ ID
  				NO: 5269)
  hCV8824241	G/A	AACAGAAAACGAAGTGATCATC	TAACAGAAAACGAAGTGATCATT	AGTTCAAGACGGGTCATATTC
  		(SEQ ID NO: 5270)	(SEQ ID NO: 5271)	(SEQ ID NO: 5272)
  hCV8824244	C/T	CCTGTTGACTGACTCATAGGG	TCCTGTTGACTGACTCATAGGA	TTGGCCACATGTTCTATCTCTA
  		(SEQ ID NO: 5273)	(SEQ ID NO: 5274)	(SEQ ID NO: 5275)
  hCV8824248	A/G	AAAGCATAGGATGGGGACA	AGCATAGGATGGGGACG	CCTGGGTGACAGAGTGAGATTT
  		(SEQ ID NO: 5276)	(SEQ ID NO: 5277)	(SEQ ID
  				NO: 5278)
  hCV8824394	G/T	GTGAGTGTGATTTTGCTCAAC	TGTGAGTGTGATTTTGCTCAAA	CCCAAACCCCCAGAGAATAAGT
  		(SEQ ID NO: 5279)	(SEQ ID NO: 5280)	(SEQ ID
  				NO: 5281)
  hCV8824424	A/G	CATGGTGACCCCACATT	CATGGTGACCCCACATC	CCCACACAGCATGCTTTCTGAAT
  		(SEQ ID NO: 5282)	(SEQ ID NO: 5283)	(SEQ ID
  				NO: 5284)
  hCV8824425	A/C	GTTGGGATAGGCTTGTTTTGT	TTGGGATAGGCTTGTTTTGG	GCCTCCCTGTGAACAAACTAAAGT
  		(SEQ ID NO: 5285)	(SEQ ID NO: 5286)	(SEQ ID
  				NO: 5287)
  hCV8824453	G/T	TCCCTGAGGTGCTGAAG	TCCCTGAGGTGCTGAAT	GGCTGGTTCTGGCTTCTTTTATCTC
  		(SEQ ID NO: 5288)	(SEQ ID NO: 5289)	(SEQ ID
  				NO: 5290)
  hCV8848630	G/T	CATCTTCATCATCAAGGGAG	CATCTTCATCATCAAGGGAT	TGTTTTCCTCCCTCAGATATCT
  		(SEQ ID NO: 5291)	(SEQ ID NO: 5292)	(SEQ ID NO: 5293)
  hCV8851047	T/C	CCTCAAAGGAAAAGGCTT	CCTCAAAGGAAAAGGCTC	GCGGACCATGTGTCAACT
  		(SEQ ID NO: 5294)	(SEQ ID NO: 5295)	(SEQ ID NO: 5296)
  hCV8851065	C/G	CCCCGCAGAGAATTACC	CCCCGCAGAGAATTACG	ACGTCGCTGTCGAAGC
  		(SEQ ID NO: 5297)	(SEQ ID NO: 5298)	(SEQ ID NO: 5299)
  hCV8851085	A/G	GCTCGTAGTTGTGTCTGCAT	GCTCGTAGTTGTGTCTGCAC	CGCTTCCTGGAGAGATACAT
  		(SEQ ID NO: 5300)	(SEQ ID NO: 5301)	(SEQ ID NO: 5302)
  hCV8851095	C/T	CTCCACTTGGCAGG	GCTCCACTTGGCAGA	CACCAACCTGATCCGTAATG
  		(SEQ ID NO: 5303)	(SEQ ID NO: 5304)	(SEQ ID NO: 5305)
  hCV8881160	C/T	TCCTAGAACATACAACA	TCCTAGAACATACAAC	GTGCCTAGCAGATGCC
  		GTTTTAGC	AGTTTTAGT	CAATAAATA
  		(SEQ ID NO: 5306)	(SEQ ID NO: 5307)	(SEQ ID
  				NO: 5308)
  hCV8881161	A/G	GAGAAAGTCCTCTATGA	GAGAAAGTCCTCTATG	CCCCGTCTTTCTTA
  		ACTGATAA	AACTGATAG	TATGAAG
  		(SEQ ID NO: 5309)	(SEQ ID NO: 5310)	GGTAGAA (SEQ ID
  				NO: 5311)
  hCV8881164	C/T	AGAACACAAAATTTCTG	AAGAACACAAAATTTCT	GATCCTCCCGGGC
  		TGATACAC	GTGATACAT	TCAAGT
  		(SEQ ID NO: 5312)	(SEQ ID NO: 5313)	(SEQ ID NO: 5314)
  hCV8888179	C/T	GCCCTCTGCACACCTTC	GCCCTCTGCACACCTTT	GGTAGGAGGATCTGCAGTTGT
  		(SEQ ID NO: 5315)	(SEQ ID NO: 5316)	(SEQ ID NO: 5317)
  hCV8892418	A/G	GAGACCAGTCTGACTTACACT	AGACCAGTCTGACTTACACC	GCCCGGCCTTCCTAGTATT
  		(SEQ ID NO: 5318)	(SEQ ID NO: 5319)	(SEQ ID NO: 5320)
  hCV8895373	A/G	AGGACTTCCGTGTCTT	AGGACTTCCGTGTCTC	ACAGATGCCAGCAATACAGA
  		(SEQ ID NO: 5321)	(SEQ ID NO: 5322)	(SEQ ID NO: 5323)
  hCV8901525	G/A	CAGCTCACGCAGCG	TCAGCTCACGCAGCA	CTTGTTGGAGTGTGTGAATAAGA
  		(SEQ ID NO: 5324)	(SEQ ID NO: 5325)	(SEQ ID
  				NO: 5326)
  hCV8921288	C/A	CCGCAGAGGTGTGGG	CCGCAGAGGTGTGGT	CATTTTGCGGTGGAAATG
  		(SEQ ID NO: 5327)	(SEQ ID NO: 5328)	(SEQ ID NO: 5329)
  hCV8936042	C/T	ACGAGAATCTTCTCCTACACG	ACGAGAATCTTCTCCTACACA	GTGTGACCCACTCTTGAAAGACAT
  		(SEQ ID NO: 5330)	(SEQ ID NO: 5331)	(SEQ ID
  				NO: 5332)
  hCV904973	C/T	TCCTCCGCGATGCCGAT	TCCTCCGCGATGCCGATG	TCGCGGGCCCCGGCCT
  		GACCTGCAGAATC	ACCTGCAGAATT	GGTACA
  		(SEQ ID NO: 5333)	(SEQ ID NO: 5334)	(SEQ ID NO: 5335)
  hCV904974	C/T	GCCGGCACTCTCTTCC	GCCGGCACTCTCTTCT	CAGAGGGACAAGCAGATGT
  		(SEQ ID NO: 5336)	(SEQ ID NO: 5337)	(SEQ ID NO: 5338)
  hCV9055799	C/G	ACAGATCCATTTCATCTAGGTC	ACAGATCCATTTCATCTAGGTC	GGCTCTGGGAATTTCACAT
  		(SEQ ID NO: 5339)	(SEQ ID NO: 5340)	(SEQ ID NO: 5341)
  hCV9077561	G/A	AGAAGGTGGGATCCAAAC	AGAAGGTGGGATCCAAAT	AGAAACCATCATGCTGAGGT
  		(SEQ ID NO: 5342)	(SEQ ID NO: 5343)	(SEQ ID NO: 5344)
  hCV922535	A/G	AAACCAAGACTCTGGCAAAT	AACCAAGACTCTGGCAAAC	TTCCCAGCTGACCCAGTTCT
  		(SEQ ID NO: 5345)	(SEQ ID NO: 5346)	(SEQ ID NO: 5347)
  hCV9326822	C/T	CTCGGGACCAGTCCAG	CTCGGGACCAGTCCAA	CCGACAGCCGAGGAGA
  		(SEQ ID NO: 5348)	(SEQ ID NO: 5349)	(SEQ ID NO: 5350)
  hCV9494470	G/T	AGGGATCCGCAAAGC	CAGGGATCCGCAAAGA	TCTTTCTGCCAGGTACATCA
  		(SEQ ID NO: 5351)	(SEQ ID NO: 5352)	(SEQ ID NO: 5353)
  hCV9506149	A/T	CTGCTGGCCGTCCT	TGCTGGCCGTCCA	ACTCACGCTTGCTTTGACT
  		(SEQ ID NO: 5354)	(SEQ ID NO: 5355)	(SEQ ID NO: 5356)
  hCV9528413	G/C	GTCGTCCTGCTGATTTCC	TCGTCCTGCTGATTTCG	GGAAGGCCGGGATACTC
  		(SEQ ID NO: 5357)	(SEQ ID NO: 5358)	(SEQ ID NO: 5359)
  hCV9549398	A/G	TCCTGCACTGTATGA	CCTGCACTGTATGATA	CAAAAGTCAACAAAT
  		TATATGTGA	TATGTGG	GTGTTTACATA
  		(SEQ ID NO: 5360)	(SEQ ID NO: 5361)	(SEQ ID
  				NO: 5362)
  hCV9581635	C/G	CTGGAGTAATAACAGGAATACTGTC	CTGGAGTAATAACAGG	CACTGCAAGTCTGTC
  		(SEQ ID NO: 5363)	AATACTGTC	TCACATAGGA
  			(SEQ ID NO: 5364)	(SEQ ID
  				NO: 5365)
  hCV9588862	C/T	AGCTGAGGGAACAAT	AAGCTGAGGGAACAA	GCCACCTGGGAAAGG
  		ATTAACG	TATTAACA	CTAAAT
  		(SEQ ID NO: 5366)	(SEQ ID NO: 5367)	(SEQ ID NO: 5368)
  hCV9589513	C/G	GTGATGGATGCCACTGTC	TGATGGATGCCACTGTG	CCTGAGTTTTTTGAC
  		(SEQ ID NO: 5369)	(SEQ ID NO: 5370)	ACATCTCT
  				(SEQ ID
  				NO: 5371)
  hCV9596963	A/G	TGCCCCCAGCCAGAA	TGCCCCCAGCCAGAG	GGCCCTCCAGGATCTG
  		(SEQ ID NO: 5372)	(SEQ ID NO: 5373)	(SEQ ID NO: 5374)
  hCV9604851	A/G	CCGCCTTGCAGATGAT	CCGCCTTGCAGATGAC	GGAGCTGGCCATTAGAATC
  		(SEQ ID NO: 5375)	(SEQ ID NO: 5376)	(SEQ ID NO: 5377)
  hCV997884	A/G	CGGTGTCAGCACCTTTGA	GGTGTCAGCACCTTTGG	CCCCCAAGCAACCACA
  		(SEQ ID NO: 5378)	(SEQ ID NO: 5379)	(SEQ ID NO: 5380)
  hDV68873046	A/T	TGGGATGAATTCTTCAA	TGGGATGAATTCTTCAA	TGCTGGTGCCTGTACCT
  		TGATAAGAT	TGATAAGAA	(SEQ ID NO: 5383)
  		(SEQ ID	(SEQ ID NO: 5382)
  		NO: 5381)
  hDV70661573	A/T	CCTGTGGTCGCCATCAA	CCTGTGGTCGCCATCAT	TTCAGGCTGTTCAGACAGTAGTG
  		(SEQ ID NO: 5384)	(SEQ ID NO: 5385)	(SEQ ID
  				NO: 5386)
  hDV70715669	A/T	GATTTGATTGGAGTCCAGGAAA	GATTTGATTGGAGTCCAGGAAT	CTGCTCCCAGCTCCAGTTTATC
  		(SEQ ID NO: 5387)	(SEQ ID NO: 5388)	(SEQ ID NO: 5389)
  hDV70751699	A/T	GGGCCATTTCTGCTGTA	GGGCCATTTCTGCTGTT	CCAGACCCCAACTCAGTAGTAGAT
  		(SEQ ID NO: 5390)	(SEQ ID NO: 5391)	(SEQ ID
  				NO: 5392)
  hDV70751704	A/T	CTCTTCTCGCCCCAGA	CTCTTCTCGCCCCAGT	AGAACACAGGCTTACACGCTTTTC
  		(SEQ ID NO: 5393)	(SEQ ID NO: 5394)	(SEQ ID
  				NO: 5395)
  hDV70751706	C/G	GTGGCTTCGTCATGTAGG	GTGGCTTCGTCATGTAGC	CGTGTAAGCCTGTGTTCTTTCTGAA
  		(SEQ ID NO: 5396)	(SEQ ID NO: 5397)	(SEQ ID
  				NO: 5398)
  hDV70797856	C/T	AAAGGTGCAAAACATCCAATTC	GAAAGGTGCAAAACATCCAATTT	CCCAGGCTAGTCTTGAACTTCT
  		(SEQ ID NO: 5399)	(SEQ ID NO: 5400)	(SEQ ID NO: 5401)
  hDV70938014	A/G	ACTTTCGTCCTCTTCATACCTA	CTTTCGTCCTCTTCATACCTG	GGGGTTCACTCTTGGTACCTTCTT
  		(SEQ ID NO: 5402)	(SEQ ID NO: 5403)	(SEQ ID
  				NO: 5404)
  hDV70973697	C/T	GCCATGAGACATAACATGCTTC	GCCATGAGACATAACATGCTTT	CGGCTTAAGGCAGAACATTTAGAGA
  		(SEQ ID NO: 5405)	(SEQ ID NO: 5406)	(SEQ ID
  				NO: 5407)
  hDV70977122	A/G	GGACAGTGGTGCTAGTAGTT	GGACAGTGGTGCTAGTAGTC	ACCCTGACCACTCTGGAACATAC
  		(SEQ ID NO: 5408)	(SEQ ID NO: 5409)	(SEQ ID
  				NO: 5410)
  hDV76976592	A/G	CTTCCAGAAAGCTCTGGGA	TCCAGAAAGCTCTGGGG	CAGGTCAACAGAGCCTACGAATAAT
  		(SEQ ID NO: 5411)	(SEQ ID NO: 5412)	(SEQ ID
  				NO: 5413)

• TABLE 6
  Interrogated SNP	Interrogated SNP	LD SNP	LD SNP
  (hCV #)	(rs #)	(hCV #)	(rs #)	Power	Threshold r2	r2

  hCV10048483	rs2145270	hCV10048484	rs1000972	0.51	0.9	0.9242
  hCV10048483	rs2145270	hCV10048501	rs979012	0.51	0.9	0.9242
  hCV10048483	rs2145270	hCV2513354	rs6054427	0.51	0.9	1
  hCV1026586	rs673548	hCV11168489	rs2678379	0.51	0.9	1
  hCV1026586	rs673548	hCV11168524	rs6544366	0.51	0.9	0.9441
  hCV1026586	rs673548	hCV11168530	rs6728178	0.51	0.9	0.9441
  hCV1026586	rs673548	hCV260164	rs6754295	0.51	0.9	0.9441
  hCV1026586	rs673548	hCV30847428	rs11902417	0.51	0.9	0.9441
  hCV1026586	rs673548	hCV3216558	rs676210	0.51	0.9	1
  hCV1026586	rs673548	hCV7615376	rs1042034	0.51	0.9	0.9709
  hCV11170747	rs2066853	hCV15956280	rs2237297	0.51	0.9	1
  hCV11170747	rs2066853	hCV16163703	rs2074113	0.51	0.9	1
  hCV11170747	rs2066853	hCV29793055	rs10274243	0.51	0.9	1
  hCV11231076	rs4857855	hCV487869	rs4431128	0.51	0.9	1
  hCV11398434	rs1812457	hCV11398437	rs1817367	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV11675962	rs10746481	0.51	0.515519235	0.9381
  hCV11398434	rs1812457	hCV1188731	rs4908514	0.51	0.515519235	0.8094
  hCV11398434	rs1812457	hCV1188735	rs10864366	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV15882429	rs2289732	0.51	0.515519235	0.5975
  hCV11398434	rs1812457	hCV15932991	rs2781067	0.51	0.515519235	0.5861
  hCV11398434	rs1812457	hCV27157507	rs6664000	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV27157524	rs6577531	0.51	0.515519235	0.7539
  hCV11398434	rs1812457	hCV2741759	rs11121179	0.51	0.515519235	0.5747
  hCV11398434	rs1812457	hCV27884601	rs4908776	0.51	0.515519235	0.8089
  hCV11398434	rs1812457	hCV27958354	rs4908762	0.51	0.515519235	0.8759
  hCV11398434	rs1812457	hCV28023091	rs4908773	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV29368919	rs4908513	0.51	0.515519235	0.8094
  hCV11398434	rs1812457	hCV2943451	rs902355	0.51	0.515519235	0.6736
  hCV11398434	rs1812457	hCV2943853	rs301793	0.51	0.515519235	0.5975
  hCV11398434	rs1812457	hCV2966436	rs11121174	0.51	0.515519235	0.5975
  hCV11398434	rs1812457	hCV2966437	rs11580417	0.51	0.515519235	0.5975
  hCV11398434	rs1812457	hCV2966441	rs6684863	0.51	0.515519235	0.5975
  hCV11398434	rs1812457	hCV2966444	rs11121171	0.51	0.515519235	0.6417
  hCV11398434	rs1812457	hCV29819064	rs6698079	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV2987250	rs301810	0.51	0.515519235	0.7861
  hCV11398434	rs1812457	hCV29873524	rs7533113	0.51	0.515519235	0.8094
  hCV11398434	rs1812457	hCV29873526	rs6697997	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV29945430	rs7517436	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV30035535	rs7518204	0.51	0.515519235	0.8087
  hCV11398434	rs1812457	hCV30125699	rs4581300	0.51	0.515519235	0.8759
  hCV11398434	rs1812457	hCV30143725	rs6690050	0.51	0.515519235	0.9381
  hCV11398434	rs1812457	hCV30467730	rs6702457	0.51	0.515519235	0.9381
  hCV11398434	rs1812457	hCV3086930	rs6658881	0.51	0.515519235	0.9345
  hCV11398434	rs1812457	hCV3086932	rs7533442	0.51	0.515519235	0.9345
  hCV11398434	rs1812457	hCV3086950	rs4908771	0.51	0.515519235	0.9381
  hCV11398434	rs1812457	hCV3086961	rs6703577	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV3086971	rs6679948	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV3086972	rs6688329	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV3086998	rs7530863	0.51	0.515519235	0.8759
  hCV11398434	rs1812457	hCV3087000	rs1463055	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV3087003	rs6577500	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV3087015	rs11121198	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV3087016	rs2297867	0.51	0.515519235	0.8759
  hCV11398434	rs1812457	hCV32055284	rs12079653	0.51	0.515519235	0.6858
  hCV11398434	rs1812457	hCV32055470	rs6577506	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV32055474	rs10864359	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV32055477	rs10779705	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV32055527	rs10864364	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV32055548	rs11121197	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV32055579	rs6577522	0.51	0.515519235	0.8092
  hCV11398434	rs1812457	hCV32055595	rs6577524	0.51	0.515519235	0.8094
  hCV11398434	rs1812457	hCV32055596	rs6577525	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV32055625	rs6678590	0.51	0.515519235	0.7684
  hCV11398434	rs1812457	hCV32055637	rs6577532	0.51	0.515519235	0.7394
  hCV11398434	rs1812457	hCV32055662	rs6677249	0.51	0.515519235	0.5758
  hCV11398434	rs1812457	hCV32055677	rs10864355	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV529178	rs301811	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV529182	rs301800	0.51	0.515519235	0.6217
  hCV11398434	rs1812457	hCV597227	rs301809	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV597229	rs301785	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV877241	rs301788	0.51	0.515519235	0.5747
  hCV11398434	rs1812457	hCV8823713	rs1472228	0.51	0.515519235	0.7979
  hCV11398434	rs1812457	hCV8824288	rs910582	0.51	0.515519235	0.8824
  hCV11398434	rs1812457	hCV8824394	rs1443929	0.51	0.515519235	0.5747
  hCV11398434	rs1812457	hCV8824424	rs1058790	0.51	0.515519235	0.6417
  hCV11398434	rs1812457	hCV8824425	rs1058791	0.51	0.515519235	0.62
  hCV11398434	rs1812457	hCV8881145	rs1038008	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV8881146	rs1463054	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV8881157	rs1535158	0.51	0.515519235	1
  hCV11398434	rs1812457	hCV8881161	rs926951	0.51	0.515519235	0.8759
  hCV11398437	rs1817367	hCV11398434	rs1812457	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV11675962	rs10746481	0.51	0.883097369	0.9276
  hCV11398437	rs1817367	hCV27958354	rs4908762	0.51	0.883097369	0.8987
  hCV11398437	rs1817367	hCV29819064	rs6698079	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV30125699	rs4581300	0.51	0.883097369	0.8936
  hCV11398437	rs1817367	hCV30143725	rs6690050	0.51	0.883097369	0.9276
  hCV11398437	rs1817367	hCV30467730	rs6702457	0.51	0.883097369	0.9276
  hCV11398437	rs1817367	hCV3086950	rs4908771	0.51	0.883097369	0.9276
  hCV11398437	rs1817367	hCV3086961	rs6703577	0.51	0.883097369	0.9642
  hCV11398437	rs1817367	hCV3086971	rs6679948	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV3086972	rs6688329	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV3086998	rs7530863	0.51	0.883097369	0.8987
  hCV11398437	rs1817367	hCV32055470	rs6577506	0.51	0.883097369	0.9642
  hCV11398437	rs1817367	hCV32055474	rs10864359	0.51	0.883097369	0.8987
  hCV11398437	rs1817367	hCV32055477	rs10779705	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV8881145	rs1038008	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV8881146	rs1463054	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV8881157	rs1535158	0.51	0.883097369	1
  hCV11398437	rs1817367	hCV8881161	rs926951	0.51	0.883097369	0.8987
  hCV11438723	rs1877273	hCV15830836	rs2859641	0.51	0.9	1
  hCV11438723	rs1877273	hCV15868592	rs2941949	0.51	0.9	0.9549
  hCV11438723	rs1877273	hCV15912032	rs2667617	0.51	0.9	0.9549
  hCV11438723	rs1877273	hCV15912048	rs2667611	0.51	0.9	0.9549
  hCV11438723	rs1877273	hCV15912085	rs2667632	0.51	0.9	1
  hCV11438723	rs1877273	hCV15912105	rs2667623	0.51	0.9	1
  hCV11438723	rs1877273	hCV1592156	rs2738745	0.51	0.9	0.9549
  hCV11438723	rs1877273	hCV1592157	rs2667614	0.51	0.9	1
  hCV11438723	rs1877273	hCV1592158	rs3106331	0.51	0.9	1
  hCV11438723	rs1877273	hCV16290607	rs2738494	0.51	0.9	1
  hCV11438723	rs1877273	hCV16290609	rs2257074	0.51	0.9	1
  hCV11438723	rs1877273	hCV16291171	rs2738743	0.51	0.9	0.9082
  hCV11438723	rs1877273	hCV27271636	rs2941952	0.51	0.9	1
  hCV11438723	rs1877273	hCV8897017	rs2859644	0.51	0.9	1
  hCV11438723	rs1877273	hCV8897018	rs1105313	0.51	0.9	1
  hCV11446935	rs2409722	hCV231938	rs7813802	0.51	0.9	0.9623
  hCV11446935	rs2409722	hCV30011529	rs7819412	0.51	0.9	1
  hCV11568688	rs1317538	hCV502935	rs12526735	0.51	0.9	1
  hCV11568668	rs1317538	hCV502936	rs1317537	0.51	0.9	0.9429
  hCV11592758	rs6265	hCV12035465	rs2049045	0.51	0.9	1
  hCV11592758	rs6265	hCV30726493	rs11030084	0.51	0.9	1
  hCV11678789	rs7219148	hCV2536560	rs11078773	0.51	0.9	1
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  hCV11864162	rs1167998	hCV32220469	rs10889332	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV32220470	rs11207974	0.51	0.9	1
  hCV11854162	rs1167998	hCV32220491	rs11577840	0.51	0.9	1
  hCV11864162	rs1167998	hCV32220495	rs11207969	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV408090	rs1183260	0.51	0.9	1
  hCV11864162	rs1167998	hCV445207	rs1627591	0.51	0.9	1
  hCV11864162	rs1167998	hCV71419	rs2131925	0.51	0.9	1
  hCV11864162	rs1167998	hCV857102	rs624660	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV857103	rs636497	0.51	0.9	0.9585
  hCV11864162	rs1167998	hCV857104	rs636523	0.51	0.9	0.959
  hCV11864162	rs1167998	hCV857108	rs597078	0.51	0.9	1
  hCV11864162	rs1167998	hCV857109	rs597470	0.51	0.9	1
  hCV11864162	rs1167998	hCV857110	rs583609	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV857121	rs642845	0.51	0.9	1
  hCV11864162	rs1167998	hCV857122	rs656297	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV857123	rs638305	0.51	0.9	1
  hCV11854162	rs1167998	hCV857127	rs631106	0.51	0.9	0.9585
  hCV11864162	rs1167998	hCV9508668	rs1781195	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV9581062	rs998403	0.51	0.9	0.958
  hCV11864162	rs1167998	hCV9581551	rs1168040	0.51	0.9	0.9364
  hCV11864162	rs1167998	hCV9581570	rs1168036	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581571	rs1002687	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581580	rs1168032	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581581	rs1168030	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581590	rs1168018	0.51	0.9	0.979
  hCV11864162	rs1167998	hCV9581606	rs1168022	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581615	rs1748201	0.51	0.9	0.979
  hCV11864162	rs1167998	hCV9581635	rs1748195	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV9581636	rs3850634	0.51	0.9	0.9585
  hCV11854162	rs1167998	hCV9581680	rs1748197	0.51	0.9	1
  hCV11864162	rs1167998	hCV9581691	rs1570694	0.51	0.9	0.9585
  hCV11864162	rs1167998	hCV9583244	rs783291	0.51	0.9	1
  hCV11864162	rs1167998	hCV9588770	rs1007205	0.51	0.9	1
  hCV11864162	rs1167998	hCV9588793	rs1168009	0.51	0.9	0.9789
  hCV11864162	rs1167998	hCV9588794	rs1168010	0.51	0.9	0.9787
  hCV11864162	rs1167998	hCV9588829	rs1781212	0.51	0.9	1
  hCV11864162	rs1167998	hCV9588850	rs1168013	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV9588862	rs995000	0.51	0.9	0.9585
  hCV11864162	rs1167998	hCV9588875	rs1168086	0.51	0.9	0.9551
  hCV11864162	rs1167998	hCV9588886	rs1168089	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV9588930	rs1168099	0.51	0.9	0.9791
  hCV11864162	rs1167998	hCV9588985	rs1168124	0.51	0.9	1
  hCV11864162	rs1167998	hDV75176134	rs1781221	0.51	0.9	1
  hCV1188731	rs4908514	hCV1188735	rs10864366	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV27157507	rs6664000	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV27157524	rs6577531	0.51	0.902764173	0.9353
  hCV1188731	rs4908514	hCV27884601	rs4908776	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV28023091	rs4908773	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV29368919	rs4908513	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV29873524	rs7533113	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV29945430	rs7517436	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV30035535	rs7518204	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV32055527	rs10864364	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV32055579	rs6577522	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV32055595	rs6577524	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV32055596	rs6577525	0.51	0.902764173	1
  hCV1188731	rs4908514	hCV32055637	rs6577532	0.51	0.902764173	0.9314
  hCV1188731	rs4908514	hCV8823713	rs1472228	0.51	0.902764173	1
  hCV1188735	rs10864366	hCV1188731	rs4908514	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV27157507	rs6664000	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV27157524	rs6577531	0.51	0.900202572	0.9314
  hCV1188735	rs10864366	hCV27884601	rs4908776	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV28023091	rs4908773	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV29368919	rs4908513	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV29873524	rs7533113	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV29945430	rs7517436	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV30035535	rs7518204	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV32055527	rs10864364	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV32055579	rs6577522	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV32055595	rs6577524	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV32055596	rs6577525	0.51	0.900202572	1
  hCV1188735	rs10864366	hCV8823713	rs1472228	0.51	0.900202572	1
  hCV1188747	rs4908511	hCV11398047	rs1922983	0.51	0.490752814	0.5859
  hCV1188747	rs4908511	hCV11398445	rs1934138	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hCV11675339	rs7530745	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV11675361	rs301819	0.51	0.490752814	0.495
  hCV1188747	rs4908511	hCV11675982	rs1953827	0.51	0.490752814	0.589
  hCV1188747	rs4908511	hCV11675985	rs12136766	0.51	0.490752814	0.589
  hCV1188747	rs4908511	hCV1188706	rs2185205	0.51	0.490752814	0.8148
  hCV1188747	rs4908511	hCV1188726	rs6698830	0.51	0.490752814	0.8871
  hCV1188747	rs4908511	hCV1188748	rs12028160	0.51	0.490752814	0.9804
  hCV1188747	rs4908511	hCV1265820	rs6577488	0.51	0.490752814	0.5859
  hCV1188747	rs4908511	hCV1265823	rs1024197	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV1265830	rs7551849	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV1265841	rs10864354	0.51	0.490752814	0.5424
  hCV1188747	rs4908511	hCV1265857	rs10864356	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV1265858	rs11121194	0.51	0.490752814	0.6093
  hCV1188747	rs4908511	hCV1265860	rs6577491	0.51	0.490752814	0.5859
  hCV1188747	rs4908511	hCV1265866	rs6577496	0.51	0.490752814	0.5763
  hCV1188747	rs4908511	hCV16007535	rs2401138	0.51	0.490752814	0.6433
  hCV1188747	rs4908511	hCV27157433	rs7544052	0.51	0.490752814	0.5193
  hCV1188747	rs4908511	hCV27157435	rs7513420	0.51	0.490752814	0.5424
  hCV1188747	rs4908511	hCV27157439	rs10779704	0.51	0.490752814	0.5331
  hCV1188747	rs4908511	hCV27157529	rs1463049	0.51	0.490752814	0.6521
  hCV1188747	rs4908511	hCV27157851	rs4480384	0.51	0.490752814	0.6203
  hCV1188747	rs4908511	hCV27506877	rs3938719	0.51	0.490752814	0.4909
  hCV1188747	rs4908511	hCV27979869	rs4908760	0.51	0.490752814	0.5693
  hCV1188747	rs4908511	hCV29368911	rs6577513	0.51	0.490752814	0.6112
  hCV1188747	rs4908511	hCV29368927	rs6577499	0.51	0.490752814	0.5859
  hCV1188747	rs4908511	hCV29368929	rs6577502	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV29674579	rs7542312	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV29855298	rs6690928	0.51	0.490752814	0.9259
  hCV1188747	rs4908511	hCV29981708	rs7554486	0.51	0.490752814	0.8421
  hCV1188747	rs4908511	hCV30233466	rs7513880	0.51	0.490752814	0.8871
  hCV1188747	rs4908511	hCV30287627	rs6675443	0.51	0.490752814	0.6014
  hCV1188747	rs4908511	hCV30341660	rs6681362	0.51	0.490752814	0.6064
  hCV1188747	rs4908511	hCV30413939	rs6701331	0.51	0.490752814	0.589
  hCV1188747	rs4908511	hCV30413946	rs7537982	0.51	0.490752814	0.6203
  hCV1188747	rs4908511	hCV3086941	rs7556169	0.51	0.490752814	0.6368
  hCV1188747	rs4908511	hCV3086945	rs6695867	0.51	0.490752814	0.6695
  hCV1188747	rs4908511	hCV3086948	rs10864361	0.51	0.490752814	0.6532
  hCV1188747	rs4908511	hCV3086949	rs11121212	0.51	0.490752814	0.7081
  hCV1188747	rs4908511	hCV3086952	rs6577514	0.51	0.490752814	0.6232
  hCV1188747	rs4908511	hCV3086954	rs1463053	0.51	0.490752814	0.6047
  hCV1188747	rs4908511	hCV3086956	rs1463052	0.51	0.490752814	0.589
  hCV1188747	rs4908511	hCV3086959	rs7520025	0.51	0.490752814	0.6689
  hCV1188747	rs4908511	hCV3086965	rs1381928	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hCV3086974	rs1318218	0.51	0.490752814	0.6354
  hCV1188747	rs4908511	hCV3086976	rs11121204	0.51	0.490752814	0.5977
  hCV1188747	rs4908511	hCV3086978	rs7526171	0.51	0.490752814	0.6419
  hCV1188747	rs4908511	hCV3086981	rs6670508	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hCV3086985	rs6663123	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hCV3086990	rs11121202	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hCV3087002	rs1473420	0.51	0.490752814	0.5859
  hCV1188747	rs4908511	hCV3087004	rs2016084	0.51	0.490752814	0.4917
  hCV1188747	rs4908511	hCV3087005	rs6702060	0.51	0.490752814	0.5703
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  hCV1188747	rs4908511	hCV32055465	rs6668508	0.51	0.490752814	0.5859
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  hCV1188747	rs4908511	hCV32055489	rs10864360	0.51	0.490752814	0.7081
  hCV1188747	rs4908511	hCV32055490	rs6669503	0.51	0.490752814	0.574
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  hCV1188747	rs4908511	hCV32055498	rs4908507	0.51	0.490752814	0.6692
  hCV1188747	rs4908511	hCV32055554	rs12024032	0.51	0.490752814	0.9804
  hCV1188747	rs4908511	hCV32055587	rs10864367	0.51	0.490752814	0.8871
  hCV1188747	rs4908511	hCV32055588	rs12131864	0.51	0.490752814	0.574
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  hCV1188747	rs4908511	hCV32056071	rs11121201	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV32392515	rs4908505	0.51	0.490752814	0.6532
  hCV1188747	rs4908511	hCV597221	rs301814	0.51	0.490752814	0.574
  hCV1188747	rs4908511	hCV8379452	rs4908781	0.51	0.490752814	0.7134
  hCV1188747	rs4908511	hCV8881153	rs1061039	0.51	0.490752814	0.6427
  hCV1188747	rs4908511	hDV75072264	rs12403640	0.51	0.490752814	0.9612
  hCV1188747	rs4908511	hDV77058075	rs4908506	0.51	0.490752814	0.6368
  hCV11955747	rs9901673	hCV247220	rs6608	0.51	0.9	0.9705
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  hCV11972326	rs5988	hCV29992410	rs9502419	0.51	0.9	0.9512
  hCV11972326	rs5988	hCV30190386	rs9504681	0.51	0.9	0.9021
  hCV11972326	rs5988	hCV30460540	rs9504684	0.51	0.9	0.9496
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  hCV11972326	rs5988	hCV31360344	rs4960170	0.51	0.9	1
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  hCV11972326	rs5988	hCV31360444	rs12181800	0.51	0.9	0.9527
  hCV11972326	rs5988	hDV77006766	rs4463306	0.51	0.9	1
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  hCV1243283	rs1716	hCV11679326	rs2976234	0.51	0.9	0.9342
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  hCV1243283	rs1716	hCV3211391	rs220461	0.51	0.9	0.9337
  hCV1253630	rs2071307	hCV1253631	rs2239691	0.51	0.9	0.9801
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  hCV1323634	rs287475	hCV1323632	rs287479	0.51	0.9	1
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  hCV1323634	rs287475	hCV1323659	rs287360	0.51	0.9	0.9252
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  hCV1323669	rs287354	hCV1323632	rs287479	0.51	0.9	0.9244
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  hCV1323669	rs287354	hCV1323670	rs167000	0.51	0.9	0.9407
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  hCV1323669	rs287354	hCV1323678	rs287350	0.51	0.9	0.9796
  hCV1323669	rs287354	hCV1323680	rs12585011	0.51	0.9	0.9617
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  hCV1323669	rs287354	hCV1323696	rs11842785	0.51	0.9	0.9609
  hCV1323669	rs287354	hCV1323700	rs6562535	0.51	0.9	0.9568
  hCV1323669	rs287354	hCV1323701	rs7330307	0.51	0.9	0.96
  hCV1323669	rs287354	hCV1323702	rs7329795	0.51	0.9	0.96
  hCV1323669	rs287354	hCV1323703	rs17641312	0.51	0.9	0.9395
  hCV1323669	rs287354	hCV1323704	rs8002457	0.51	0.9	0.9401
  hCV1323669	rs287354	hCV32085644	rs12585431	0.51	0.9	0.9617
  hCV1323669	rs287354	hCV32085645	rs11842784	0.51	0.9	0.9609
  hCV1323669	rs287354	hCV615776	rs287476	0.51	0.9	0.9408
  hCV1323669	rs287354	hCV615780	rs287439	0.51	0.9	0.9408
  hCV1323669	rs287354	hCV7597674	rs287356	0.51	0.9	0.98
  hCV1345898	rs2230804	hCV11753633	rs7923726	0.51	0.9	1
  hCV1345898	rs2230804	hCV1345851	rs2270961	0.51	0.9	0.981
  hCV1345898	rs2230804	hCV1345862	rs6584354	0.51	0.9	0.9619
  hCV1345898	rs2230804	hCV1345912	rs7909855	0.51	0.9	0.9621
  hCV1345898	rs2230804	hCV1858698	rs3818411	0.51	0.9	0.981
  hCV1345898	rs2230804	hCV25592811	rs4919438	0.51	0.9	0.981
  hCV1345898	rs2230804	hCV29348491	rs7922807	0.51	0.9	0.9619
  hCV1345898	rs2230804	hCV29348492	rs7079072	0.51	0.9	0.9649
  hCV1345898	rs2230804	hCV31980317	rs12254005	0.51	0.9	1
  hCV1345898	rs2230804	hCV31980340	rs12242503	0.51	0.9	0.9619
  hCV1345898	rs2230804	hCV31980399	rs12269373	0.51	0.9	0.981
  hCV1361979	rs25683	hCV11414348	rs13202042	0.51	0.9	0.9812
  hCV1361979	rs25683	hCV1361961	rs3818299	0.51	0.9	0.9812
  hCV1361979	rs25683	hCV1361978	rs11751480	0.51	0.9	0.9621
  hCV1361979	rs25683	hCV1361983	rs13194896	0.51	0.9	1
  hCV1361979	rs25683	hCV1361988	rs3798211	0.51	0.9	0.9628
  hCV1361979	rs25683	hCV1362003	rs1440	0.51	0.9	0.9812
  hCV1361979	rs25683	hCV15818677	rs2842970	0.51	0.9	0.9648
  hCV1361979	rs25683	hCV15818688	rs2842975	0.51	0.9	0.9648
  hCV1361979	rs25683	hCV15818690	rs2842972	0.51	0.9	0.9807
  hCV1361979	rs25683	hCV16179956	rs2273828	0.51	0.9	0.9812
  hCV1361979	rs25683	hCV16191216	rs2295899	0.51	0.9	0.9812
  hCV1361979	rs25683	hCV16288760	rs2758311	0.51	0.9	0.9635
  hCV1361979	rs25683	hCV8699839	rs927450	0.51	0.9	0.9812
  hCV1375141	rs1881420	hCV11167501	rs12619135	0.51	0.9	1
  hCV1375141	rs1881420	hCV1375138	rs13428329	0.51	0.9	1
  hCV1375141	rs1881420	hCV1375139	rs4666172	0.51	0.9	0.9054
  hCV1375141	rs1881420	hCV1375144	rs2278879	0.51	0.9	1
  hCV1375141	rs1881420	hCV27505984	rs3820712	0.51	0.9	0.9054
  hCV1375141	rs1881420	hCV27513883	rs3768672	0.51	0.9	1
  hCV1375141	rs1881420	hCV30109305	rs4666176	0.51	0.9	0.9054
  hCV1375141	rs1881420	hCV32191953	rs13386033	0.51	0.9	0.9124
  hCV1375141	rs1881420	hCV9531551	rs1026277	0.51	0.9	1
  hCV1463112	rs3763608	hCV11765753	rs3793456	0.51	0.763750033	0.827
  hCV1463112	rs3763608	hCV1463244	rs3793465	0.51	0.763750033	0.8333
  hCV1463112	rs3763608	hCV1463252	rs3793461	0.51	0.763750033	0.8591
  hCV1463112	rs3763608	hCV15761059	rs2309393	0.51	0.763750033	0.8333
  hCV1463112	rs3763608	hCV26566199	rs3793467	0.51	0.763750033	0.8591
  hCV1463112	rs3763608	hCV28008078	rs4745543	0.51	0.763750033	1
  hCV1463112	rs3763608	hCV30586985	rs10126006	0.51	0.763750033	0.8497
  hCV1463112	rs3763608	hCV31363797	rs11145043	0.51	0.763750033	0.7954
  hCV1463112	rs3763608	hCV31363840	rs7875693	0.51	0.763750033	0.7758
  hCV1463112	rs3763608	hCV31363841	rs7849347	0.51	0.763750033	0.792
  hCV1463222	rs4744808	hCV11373123	rs1984003	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV11761245	rs7043149	0.51	0.343783224	0.3997
  hCV1463222	rs4744808	hCV11765727	rs10781379	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV11765729	rs7875659	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV11765753	rs3793456	0.51	0.343783224	0.7223
  hCV1463222	rs4744808	hCV1463101	rs7871596	0.51	0.343783224	0.4845
  hCV1463222	rs4744808	hCV1463112	rs3763608	0.51	0.343783224	0.5342
  hCV1463222	rs4744808	hCV1463185	rs953588	0.51	0.343783224	0.5193
  hCV1463222	rs4744808	hCV1463197	rs6560551	0.51	0.343783224	0.7657
  hCV1463222	rs4744808	hCV1463216	rs4745581	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV1463217	rs4745580	0.51	0.343783224	0.7657
  hCV1463222	rs4744808	hCV1463218	rs1984004	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV1463223	rs4744807	0.51	0.343783224	0.7609
  hCV1463222	rs4744808	hCV1463225	rs4745577	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV1463226	rs10890	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV1463229	rs7861997	0.51	0.343783224	0.7996
  hCV1463222	rs4744808	hCV1463231	rs7870295	0.51	0.343783224	0.7657
  hCV1463222	rs4744808	hCV1463232	rs9314854	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV1463235	rs2498430	0.51	0.343783224	0.4988
  hCV1463222	rs4744808	hCV1463244	rs3793465	0.51	0.343783224	0.6837
  hCV1463222	rs4744808	hCV1463247	rs3829064	0.51	0.343783224	0.5777
  hCV1463222	rs4744808	hCV1463251	rs2498434	0.51	0.343783224	0.4995
  hCV1463222	rs4744808	hCV1463252	rs3793461	0.51	0.343783224	0.6777
  hCV1463222	rs4744808	hCV1463256	rs2309394	0.51	0.343783224	0.4563
  hCV1463222	rs4744808	hCV15761059	rs2309393	0.51	0.343783224	0.6837
  hCV1463222	rs4744808	hCV15892414	rs2498431	0.51	0.343783224	0.4988
  hCV1463222	rs4744808	hCV15892430	rs2498433	0.51	0.343783224	0.3691
  hCV1463222	rs4744808	hCV25609765	rs3829062	0.51	0.343783224	0.4563
  hCV1463222	rs4744808	hCV26566199	rs3793467	0.51	0.343783224	0.6777
  hCV1463222	rs4744808	hCV26566299	rs10869821	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV27517372	rs3793457	0.51	0.343783224	0.5504
  hCV1463222	rs4744808	hCV27996874	rs4745701	0.51	0.343783224	0.3878
  hCV1463222	rs4744808	hCV28008078	rs4745543	0.51	0.343783224	0.5597
  hCV1463222	rs4744808	hCV28035790	rs4744811	0.51	0.343783224	0.7505
  hCV1463222	rs4744808	hCV29861776	rs9411171	0.51	0.343783224	0.5777
  hCV1463222	rs4744808	hCV30586985	rs10126006	0.51	0.343783224	0.6289
  hCV1463222	rs4744808	hCV31363797	rs11145043	0.51	0.343783224	0.722
  hCV1463222	rs4744808	hCV31363840	rs7875693	0.51	0.343783224	0.6922
  hCV1463222	rs4744808	hCV31363841	rs7849347	0.51	0.343783224	0.7494
  hCV1463222	rs4744808	hCV31363869	rs11145070	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV31363888	rs7859021	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV31363984	rs7855905	0.51	0.343783224	0.6837
  hCV1463222	rs4744808	hCV31364141	rs11145460	0.51	0.343783224	0.3887
  hCV1463222	rs4744808	hCV320569	rs9411170	0.51	0.343783224	0.444
  hCV1463222	rs4744808	hCV8785184	rs1411676	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV8785185	rs1411675	0.51	0.343783224	1
  hCV1463222	rs4744808	hCV9333267	rs1045632	0.51	0.343783224	1
  hCV1463222	rs4744808	hDV71871695	rs7047274	0.51	0.343783224	0.4858
  hCV1488444	rs10164405	hCV1488443	rs10409390	0.51	0.9	0.9556
  hCV1488444	rs10164405	hCV1488445	rs2020362	0.51	0.9	0.9556
  hCV1488444	rs10164405	hCV1488457	rs1529736	0.51	0.9	0.915
  hCV1488444	rs10164405	hCV27115656	rs17546075	0.51	0.9	0.9755
  hCV1488444	rs10164405	hCV27115659	rs10424169	0.51	0.9	0.9755
  hCV1488444	rs10164405	hCV27115660	rs10423958	0.51	0.9	0.9556
  hCV1488444	rs10164405	hCV27115665	rs17628547	0.51	0.9	0.9556
  hCV1488444	rs10164405	hCV27115673	rs7351092	0.51	0.9	0.9118
  hCV1488444	rs10164405	hCV29999392	rs10405722	0.51	0.9	0.9755
  hCV1488444	rs10164405	hCV30197290	rs10405541	0.51	0.9	0.9755
  hCV1488444	rs10164405	hCV30467374	rs10402416	0.51	0.9	0.9755
  hCV1488444	rs10164405	hCV3057588	rs12977165	0.51	0.9	0.9514
  hCV1488444	rs10164405	hCV3057604	rs17628655	0.51	0.9	0.9035
  hCV1488444	rs10164405	hDV70967049	rs17545436	0.51	0.9	0.9135
  hCV1488444	rs10164405	hDV70967068	rs17545624	0.51	0.9	0.9278
  hCV1488444	rs10164405	hDV70967114	rs17545970	0.51	0.9	0.9124
  hCV1488444	rs10164405	hDV70979159	rs17628152	0.51	0.9	0.9755
  hCV1488444	rs10164405	hDV70979177	rs17628232	0.51	0.9	0.9755
  hCV1488444	rs10164405	hDV75173800	rs17628099	0.51	0.9	0.9088
  hCV1489995	rs4013819	hCV1489958	rs1501572	0.51	0.9	0.9295
  hCV1489995	rs4013819	hCV1489988	rs7036937	0.51	0.9	1
  hCV1489995	rs4013819	hCV1489991	rs10968723	0.51	0.9	0.9618
  hCV1489995	rs4013819	hCV1489993	rs2134110	0.51	0.9	1
  hCV1489995	rs4013819	hCV1489996	rs10120379	0.51	0.9	0.9611
  hCV1489995	rs4013819	hCV1490005	rs7848307	0.51	0.9	0.9425
  hCV1489995	rs4013819	hCV27089552	rs7868575	0.51	0.9	0.9431
  hCV1489995	rs4013819	hCV29340958	rs7862374	0.51	0.9	0.9431
  hCV1489995	rs4013819	hCV31943333	rs12339768	0.51	0.9	0.9648
  hCV1489995	rs4013819	hCV31943390	rs10968708	0.51	0.9	0.9415
  hCV1552894	rs434473	hCV12121729	rs10852889	0.51	0.9	1
  hCV1552894	rs434473	hCV1552899	rs2292353	0.51	0.9	1
  hCV1552894	rs434473	hCV1552900	rs1126667	0.51	0.9	1
  hCV1552894	rs434473	hCV1552901	rs1042356	0.51	0.9	1
  hCV1552894	rs434473	hCV1552908	rs312466	0.51	0.9	0.9811
  hCV1552894	rs434473	hCV15867474	rs2070590	0.51	0.9	1
  hCV1552894	rs434473	hCV16195939	rs2070589	0.51	0.9	1
  hCV1552894	rs434473	hCV31413421	rs6502998	0.51	0.9	0.9435
  hCV1552894	rs434473	hCV9277205	rs6502999	0.51	0.9	0.9646
  hCV1552900	rs1126667	hCV12121729	rs10852889	0.51	0.9	1
  hCV1552900	rs1126667	hCV1552894	rs434473	0.51	0.9	1
  hCV1552900	rs1126667	hCV1552899	rs2292353	0.51	0.9	1
  hCV1552900	rs1126667	hCV1552901	rs1042356	0.51	0.9	1
  hCV1552900	rs1126667	hCV1552908	rs312466	0.51	0.9	0.9808
  hCV1552900	rs1126667	hCV15867474	rs2070590	0.51	0.9	1
  hCV1552900	rs1126667	hCV16195939	rs2070589	0.51	0.9	1
  hCV1552900	rs1126667	hCV31413421	rs6502998	0.51	0.9	0.9426
  hCV1552900	rs1126667	hCV9277205	rs6502999	0.51	0.9	0.9634
  hCV15758290	rs6716834	hCV1533428	rs2544376	0.51	0.9	0.9765
  hCV15758290	rs6716834	hCV8822225	rs2544377	0.51	0.9	1
  hCV15758290	rs6716834	hCV8822233	rs861239	0.51	0.9	1
  hCV15758290	rs6716834	hCV95255	rs2544381	0.51	0.9	0.9776
  hCV15758290	rs6716834	hCV95256	rs2544380	0.51	0.9	1
  hCV15851779	rs2230009	hCV12105879	rs2037962	0.51	0.9	1
  hCV15851779	rs2230009	hCV15793665	rs3087418	0.51	0.9	1
  hCV15851779	rs2230009	hCV25471760	rs3087409	0.51	0.9	1
  hCV15851779	rs2230009	hCV25921517	rs3213197	0.51	0.9	1
  hCV15851779	rs2230009	hCV25921527	rs4987239	0.51	0.9	1
  hCV15851779	rs2230009	hCV27829132	rs11574175	0.51	0.9	1
  hCV15851779	rs2230009	hCV31337210	rs11574400	0.51	0.9	0.9286
  hCV15851779	rs2230009	hCV31674015	rs11574266	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674023	rs7829687	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674032	rs11574260	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674034	rs11574259	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674062	rs11574238	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674064	rs11574235	0.51	0.9	0.9327
  hCV15851779	rs2230009	hCV31674067	rs11574227	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674074	rs11574220	0.51	0.9	1
  hCV15851779	rs2230009	hCV31674103	rs7003607	0.51	0.9	1
  hCV15851779	rs2230009	hDV70705670	rs16877715	0.51	0.9	1
  hCV15870728	rs2943245	hCV3033539	rs2663041	0.51	0.9	0.9342
  hCV15870728	rs2943245	hCV3033560	rs2671694	0.51	0.9	0.9319
  hCV15876011	rs2228541	hCV1260386	rs8005533	0.51	0.9	1
  hCV15876011	rs2228541	hCV1260388	rs11160169	0.51	0.9	1
  hCV15876011	rs2228541	hCV30012503	rs10498639	0.51	0.9	0.9628
  hCV15876011	rs2228541	hCV30246438	rs8023023	0.51	0.9	1
  hCV15876011	rs2228541	hCV31536164	rs11627651	0.51	0.9	1
  hCV15876011	rs2228541	hCV31536166	rs11622970	0.51	0.9	1
  hCV15892430	rs2498433	hCV11765753	rs3793456	0.51	0.49786513	0.5315
  hCV15892430	rs2498433	hCV1463101	rs7871596	0.51	0.49786513	0.6974
  hCV15892430	rs2498433	hCV1463197	rs6560551	0.51	0.49786513	0.5544
  hCV15892430	rs2498433	hCV1463217	rs4745580	0.51	0.49786513	0.5544
  hCV15892430	rs2498433	hCV1463223	rs4744807	0.51	0.49786513	0.5544
  hCV15892430	rs2498433	hCV1463229	rs7861997	0.51	0.49786513	0.5055
  hCV15892430	rs2498433	hCV1463231	rs7870295	0.51	0.49786513	0.5544
  hCV15892430	rs2498433	hCV1463235	rs2498430	0.51	0.49786513	0.7645
  hCV15892430	rs2498433	hCV1463247	rs3829064	0.51	0.49786513	0.7486
  hCV15892430	rs2498433	hCV1463251	rs2498434	0.51	0.49786513	0.7304
  hCV15892430	rs2498433	hCV1463252	rs3793461	0.51	0.49786513	0.608
  hCV15892430	rs2498433	hCV1463256	rs2309394	0.51	0.49786513	0.7999
  hCV15892430	rs2498433	hCV15892414	rs2498431	0.51	0.49786513	0.7645
  hCV15892430	rs2498433	hCV25609765	rs3829062	0.51	0.49786513	0.7999
  hCV15892430	rs2498433	hCV26566199	rs3793467	0.51	0.49786513	0.608
  hCV15892430	rs2498433	hCV27517372	rs3793457	0.51	0.49786513	0.7181
  hCV15892430	rs2498433	hCV28008078	rs4745543	0.51	0.49786513	0.5053
  hCV15892430	rs2498433	hCV28035790	rs4744811	0.51	0.49786513	0.5181
  hCV15892430	rs2498433	hCV29861776	rs9411171	0.51	0.49786513	0.7486
  hCV15892430	rs2498433	hCV30586985	rs10126006	0.51	0.49786513	0.5477
  hCV15892430	rs2498433	hCV31363797	rs11145043	0.51	0.49786513	0.5225
  hCV15892430	rs2498433	hCV31363840	rs7875693	0.51	0.49786513	0.5159
  hCV15892430	rs2498433	hCV31363841	rs7849347	0.51	0.49786513	0.556
  hCV15892430	rs2498433	hCV31363984	rs7855905	0.51	0.49786513	0.5225
  hCV15892430	rs2498433	hCV320569	rs9411170	0.51	0.49786513	0.7647
  hCV15892430	rs2498433	hDV71871695	rs7047274	0.51	0.49786513	0.7304
  hCV15954277	rs2236379	hCV1872594	rs1886050	0.51	0.9	1
  hCV15954277	rs2236379	hCV27483955	rs3793729	0.51	0.9	0.9075
  hCV15954645	rs2954029	hCV11593303	rs2980871	0.51	0.9	0.9306
  hCV15954645	rs2954029	hCV12004940	rs2001844	0.51	0.9	0.9655
  hCV15954645	rs2954029	hCV15883779	rs2980869	0.51	0.9	0.9634
  hCV15954645	rs2954029	hCV15883790	rs2980875	0.51	0.9	1
  hCV15954645	rs2954029	hCV15954624	rs2954022	0.51	0.9	1
  hCV15954645	rs2954029	hCV26372062	rs2980856	0.51	0.9	0.9634
  hCV15954645	rs2954029	hCV26372064	rs2980855	0.51	0.9	0.9655
  hCV15954645	rs2954029	hCV26372065	rs2980854	0.51	0.9	0.9655
  hCV15954645	rs2954029	hCV26372066	rs2980853	0.51	0.9	0.9634
  hCV15954645	rs2954029	hCV26372069	rs2980882	0.51	0.9	0.9655
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  hCV15954645	rs2954029	hCV309481	rs2954019	0.51	0.9	0.9655
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  hCV1802755	rs7764347	hCV8769617	rs1413741	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769624	rs1413742	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769625	rs1334662	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769626	rs1334663	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769647	rs1761860	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769648	rs1761861	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769649	rs1761862	0.51	0.9	0.971
  hCV1802755	rs7764347	hCV8769656	rs1741651	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769657	rs1761865	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769665	rs1334666	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769677	rs1334667	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769688	rs1334669	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769690	rs1761874	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769713	rs1741660	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769714	rs1741661	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769723	rs1741662	0.51	0.9	1
  hCV1802755	rs7764347	hCV8769734	rs677383	0.51	0.9	1
  hCV1802755	rs7764347	hDV75232846	rs2353359	0.51	0.9	1
  hCV1948599	rs504527	hCV952816	rs495444	0.51	0.9	0.9634
  hCV2038	rs4673	hCV11291915	rs4782308	0.51	0.9	0.9561
  hCV2038	rs4673	hCV25647671	rs12933505	0.51	0.9	0.9783
  hCV207123	rs7771801	hCV103951	rs6455688	0.51	0.442309245	1
  hCV207123	rs7771801	hCV103951	rs6455688	0.51	0.608405136	1
  hCV207123	rs7771801	hCV103952	rs6923877	0.51	0.442309245	1
  hCV207123	rs7771801	hCV103952	rs6923877	0.51	0.608405136	1
  hCV207123	rs7771801	hCV11226249	rs6415085	0.51	0.442309245	0.7706
  hCV207123	rs7771801	hCV11226249	rs6415085	0.51	0.608405136	0.7706
  hCV207123	rs7771801	hCV11284288	rs9457946	0.51	0.442309245	1
  hCV207123	rs7771801	hCV11284288	rs9457946	0.51	0.608405136	1
  hCV207123	rs7771801	hCV11846435	rs6929299	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV11846435	rs6929299	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV1550866	rs6932014	0.51	0.442309245	0.7706
  hCV207123	rs7771801	hCV1550866	rs6932014	0.51	0.608405136	0.7706
  hCV207123	rs7771801	hCV1550871	rs9355295	0.51	0.442309245	1
  hCV207123	rs7771801	hCV1550871	rs9355295	0.51	0.608405136	1
  hCV207123	rs7771801	hCV207127	rs7453899	0.51	0.442309245	1
  hCV207123	rs7771801	hCV207127	rs7453899	0.51	0.608405136	1
  hCV207123	rs7771801	hCV207128	rs6455689	0.51	0.442309245	1
  hCV207123	rs7771801	hCV207128	rs6455689	0.51	0.608405136	1
  hCV207123	rs7771801	hCV243055	rs10945682	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV243055	rs10945682	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV249895	rs7771129	0.51	0.442309245	0.7706
  hCV207123	rs7771801	hCV249895	rs7771129	0.51	0.608405136	0.7706
  hCV207123	rs7771801	hCV249897	rs6913833	0.51	0.442309245	0.6956
  hCV207123	rs7771801	hCV249897	rs6913833	0.51	0.608405136	0.6956
  hCV207123	rs7771801	hCV249898	rs9456552	0.51	0.442309245	0.7815
  hCV207123	rs7771801	hCV249898	rs9456552	0.51	0.608405136	0.7815
  hCV207123	rs7771801	hCV25929408	rs7765781	0.51	0.442309245	1
  hCV207123	rs7771801	hCV25929408	rs7765781	0.51	0.608405136	1
  hCV207123	rs7771801	hCV25929478	rs7765803	0.51	0.442309245	1
  hCV207123	rs7771801	hCV25929478	rs7765803	0.51	0.608405136	1
  hCV207123	rs7771801	hCV26272389	rs7760585	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV26272389	rs7760585	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV27422546	rs7761377	0.51	0.442309245	0.7343
  hCV207123	rs7771801	hCV27422546	rs7761377	0.51	0.608405136	0.7343
  hCV207123	rs7771801	hCV27422547	rs6455696	0.51	0.442309245	0.739
  hCV207123	rs7771801	hCV27422547	rs6455696	0.51	0.608405136	0.739
  hCV207123	rs7771801	hCV27422554	rs6923917	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV27422554	rs6923917	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV27422556	rs9355814	0.51	0.442309245	0.7541
  hCV207123	rs7771801	hCV27422556	rs9355814	0.51	0.608405136	0.7541
  hCV207123	rs7771801	hCV27422557	rs9355813	0.51	0.442309245	0.7052
  hCV207123	rs7771801	hCV27422557	rs9355813	0.51	0.608405136	0.7052
  hCV207123	rs7771801	hCV29322781	rs6921516	0.51	0.442309245	1
  hCV207123	rs7771801	hCV29322781	rs6921516	0.51	0.608405136	1
  hCV207123	rs7771801	hCV29546641	rs9365171	0.51	0.442309245	0.8426
  hCV207123	rs7771801	hCV29546641	rs9365171	0.51	0.608405136	0.8426
  hCV207123	rs7771801	hCV29709361	rs9365179	0.51	0.442309245	0.7271
  hCV207123	rs7771801	hCV29709361	rs9365179	0.51	0.608405136	0.7271
  hCV207123	rs7771801	hCV29817515	rs9355817	0.51	0.442309245	0.703
  hCV207123	rs7771801	hCV29817515	rs9355817	0.51	0.608405136	0.703
  hCV207123	rs7771801	hCV29934611	rs9295130	0.51	0.442309245	0.7512
  hCV207123	rs7771801	hCV29934611	rs9295130	0.51	0.608405136	0.7512
  hCV207123	rs7771801	hCV29998162	rs9457943	0.51	0.442309245	1
  hCV207123	rs7771801	hCV29998162	rs9457943	0.51	0.608405136	1
  hCV207123	rs7771801	hCV305046	rs6902102	0.51	0.442309245	0.764
  hCV207123	rs7771801	hCV305046	rs6902102	0.51	0.608405136	0.764
  hCV207123	rs7771801	hCV3201494	rs1367209	0.51	0.442309245	0.8378
  hCV207123	rs7771801	hCV3201494	rs1367209	0.51	0.608405136	0.8378
  hCV207123	rs7771801	hCV3201497	rs1321196	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV3201497	rs1321196	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV8710154	rs1569933	0.51	0.442309245	0.7512
  hCV207123	rs7771801	hCV8710154	rs1569933	0.51	0.608405136	0.7512
  hCV207123	rs7771801	hCV8710161	rs1740428	0.51	0.442309245	0.7556
  hCV207123	rs7771801	hCV8710161	rs1740428	0.51	0.608405136	0.7556
  hCV207123	rs7771801	hCV8710162	rs1367211	0.51	0.442309245	0.8378
  hCV207123	rs7771801	hCV8710162	rs1367211	0.51	0.608405136	0.8378
  hCV207123	rs7771801	hDV77235995	rs7746273	0.51	0.442309245	0.7058
  hCV207123	rs7771801	hDV77235995	rs7746273	0.51	0.608405136	0.7058
  hCV2143205	rs9666607	hCV1622732	rs10768114	0.51	0.9	0.9787
  hCV2195496	rs4982795	hCV2195484	rs7156111	0.51	0.9	0.9811
  hCV22274679	rs3812475	hCV11595113	rs12548235	0.51	0.776093561	0.9434
  hCV22274679	rs3812475	hCV11595482	rs7830506	0.51	0.776093561	0.9811
  hCV22274679	rs3812475	hCV149577	rs10091243	0.51	0.776093561	0.9281
  hCV22274679	rs3812475	hCV149578	rs10106292	0.51	0.776093561	0.9294
  hCV22274679	rs3812475	hCV157937	rs7013683	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV1843454	rs3812472	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV26088153	rs4871498	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV27535572	rs4128468	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV29086592	rs7812911	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV30756534	rs3886003	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV314558	rs7007115	0.51	0.776093561	0.8874
  hCV22274679	rs3812475	hCV314561	rs7009290	0.51	0.776093561	0.9294
  hCV22274679	rs3812475	hCV314562	rs6982197	0.51	0.776093561	0.9434
  hCV22274679	rs3812475	hCV314563	rs4269526	0.51	0.776093561	0.9434
  hCV22274679	rs3812475	hCV314564	rs4269525	0.51	0.776093561	0.9434
  hCV22274679	rs3812475	hCV430717	rs3812471	0.51	0.776093561	1
  hCV22274679	rs3812475	hCV437982	rs4132855	0.51	0.776093561	0.7934
  hCV22274679	rs3812475	hCV47808	rs7827791	0.51	0.776093561	0.9294
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  hCV22275550	rs6836335	hCV1161362	rs11732057	0.51	0.9	1
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  hCV22275550	rs6836335	hDV71950388	rs7684536	0.51	0.9	0.9076
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  hCV2554615	rs2522057	hCV15849790	rs2188962	0.51	0.9	0.9608
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  hCV2554615	rs2522057	hCV31237910	rs12521868	0.51	0.9	0.9606
  hCV2554615	rs2522057	hCV3170459	rs1050152	0.51	0.9	0.9037
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  hCV2554721	rs7315519	hCV2554699	rs4767000	0.51	0.9	0.9596
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  hCV25610819	rs8176740	hCV997889	rs638756	0.51	0.9	0.9521
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  hCV25631989	rs1135983	hCV1498764	rs2271012	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498765	rs1910480	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498769	rs10917946	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498789	rs12405111	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498802	rs7535349	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498806	rs7530997	0.51	0.9	1
  hCV25631989	rs1135983	hCV1498820	rs955852	0.51	0.9	1
  hCV25631989	rs1135983	hCV15860707	rs2070151	0.51	0.9	1
  hCV25631989	rs1135983	hCV15860708	rs2070150	0.51	0.9	1
  hCV25631989	rs1135983	hCV15991581	rs2340823	0.51	0.9	1
  hCV25631989	rs1135983	hCV16078774	rs2879841	0.51	0.9	1
  hCV25631989	rs1135983	hCV16206436	rs2341477	0.51	0.9	1
  hCV25631989	rs1135983	hCV27471434	rs3738326	0.51	0.9	1
  hCV25631989	rs1135983	hCV27521453	rs3820489	0.51	0.9	1
  hCV25631989	rs1135983	hCV27865203	rs4657116	0.51	0.9	1
  hCV25631989	rs1135983	hCV27951691	rs4657104	0.51	0.9	1
  hCV25631989	rs1135983	hCV28016731	rs4657118	0.51	0.9	1
  hCV25631989	rs1135983	hCV29773346	rs7523416	0.51	0.9	1
  hCV25631989	rs1135983	hCV29953697	rs6687850	0.51	0.9	1
  hCV25631989	rs1135983	hCV30097926	rs7545293	0.51	0.9	1
  hCV25631989	rs1135983	hCV30349845	rs10494358	0.51	0.9	1
  hCV25631989	rs1135983	hCV30475776	rs7532457	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086840	rs10799979	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086842	rs12040648	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086843	rs6427630	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086854	rs10917955	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086864	rs4656334	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086917	rs12025560	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086921	rs12028953	0.51	0.9	1
  hCV25631989	rs1135983	hCV31086939	rs12040523	0.51	0.9	1
  hCV25631989	rs1135983	hCV31087435	rs12026445	0.51	0.9	1
  hCV25631989	rs1135983	hCV32324133	rs4657120	0.51	0.9	1
  hCV25631989	rs1135983	hCV49962	rs12402354	0.51	0.9	1
  hCV25631989	rs1135983	hCV515827	rs6427634	0.51	0.9	1
  hCV25631989	rs1135983	hCV9620270	rs1394068	0.51	0.9	1
  hCV25631989	rs1135983	hCV9620271	rs1394069	0.51	0.9	1
  hCV25631989	rs1135983	hCV9620977	rs1553443	0.51	0.9	1
  hCV25631989	rs1135983	hDV70661530	rs16863838	0.51	0.9	1
  hCV25631989	rs1135983	hDV70683947	rs16847590	0.51	0.9	1
  hCV25767417	rs3803430	hCV25473269	rs4646690	0.51	0.9	1
  hCV25767417	rs3803430	hCV27296381	rs4246326	0.51	0.9	1
  hCV25767417	rs3803430	hCV27891437	rs4246323	0.51	0.9	1
  hCV25767417	rs3803430	hCV29415509	rs4646672	0.51	0.9	1
  hCV25767417	rs3803430	hCV31591253	rs7168644	0.51	0.9	1
  hCV25767417	rs3803430	hDV77028856	rs4646680	0.51	0.9	1
  hCV25767417	rs3803430	hDV77028857	rs4646681	0.51	0.9	1
  hCV25767417	rs3803430	hDV77028859	rs4646683	0.51	0.9	1
  hCV25922816	rs36013429	hCV25769066	rs3813619	0.51	0.9	0.9031
  hCV25926771	rs4906321	hCV11660548	rs1989565	0.51	0.9	0.9616
  hCV25926771	rs4906321	hCV1292630	rs10133035	0.51	0.9	0.9039
  hCV25926771	rs4906321	hCV1292646	rs3783402	0.51	0.9	0.9107
  hCV25926771	rs4906321	hCV1292649	rs9671911	0.51	0.9	0.9227
  hCV25926771	rs4906321	hCV1292713	rs10141120	0.51	0.9	0.92
  hCV25926771	rs4906321	hCV1292762	rs7152202	0.51	0.9	0.9227
  hCV25926771	rs4906321	hCV16179592	rs2273699	0.51	0.9	0.96
  hCV25926771	rs4906321	hCV26352257	rs11621037	0.51	0.9	0.9227
  hCV25926771	rs4906321	hCV29078396	rs7158822	0.51	0.9	0.9199
  hCV25926771	rs4906321	hCV31068323	rs12898029	0.51	0.9	0.9616
  hCV25926771	rs4906321	hCV31068332	rs7158144	0.51	0.9	0.9057
  hCV25926771	rs4906321	hCV8901411	rs1028613	0.51	0.9	0.9226
  hCV25927459	rs3798221	hCV103951	rs6455688	0.51	0.47241724	0.4725
  hCV25927459	rs3798221	hCV103952	rs6923877	0.51	0.47241724	0.4725
  hCV25927459	rs3798221	hCV11285578	rs6926458	0.51	0.47241724	0.7323
  hCV25927459	rs3798221	hCV26272388	rs7770685	0.51	0.47241724	0.7365
  hCV25927459	rs3798221	hCV27422538	rs6940254	0.51	0.47241724	0.6129
  hCV25927459	rs3798221	hCV27422565	rs13202636	0.51	0.47241724	0.7365
  hCV25927459	rs3798221	hCV31882494	rs12175867	0.51	0.47241724	0.6129
  hCV25927459	rs3798221	hCV3201490	rs1321195	0.51	0.47241724	0.6526
  hCV25927459	rs3798221	hCV3201495	rs1367210	0.51	0.47241724	0.5491
  hCV25927459	rs3798221	hCV8701273	rs783148	0.51	0.47241724	0.6526
  hCV25941408	rs28497577	hCV11720681	rs1947511	0.51	0.9	1
  hCV25941408	rs28497577	hCV11720683	rs17125	0.51	0.9	1
  hCV25941408	rs28497577	hCV27912783	rs4678060	0.51	0.9	0.9239
  hCV25942539	rs2401751	hCV11474667	rs10150311	0.51	0.9	0.9163
  hCV25942539	rs2401751	hCV11474668	rs10138002	0.51	0.9	0.9163
  hCV25942539	rs2401751	hCV11474679	rs2778936	0.51	0.9	0.9591
  hCV25942539	rs2401751	hCV11666712	rs1864747	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV11666713	rs1864746	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV11666724	rs1864744	0.51	0.9	1
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  hCV25942539	rs2401751	hCV2231821	rs453112	0.51	0.9	0.9596
  hCV25942539	rs2401751	hCV2485039	rs3179969	0.51	0.9	0.9793
  hCV25942539	rs2401751	hCV25935678	rs4904452	0.51	0.9	0.9573
  hCV25942539	rs2401751	hCV27202496	rs1099698	0.51	0.9	0.9558
  hCV25942539	rs2401751	hCV27202543	rs7146241	0.51	0.9	0.9591
  hCV25942539	rs2401751	hCV29385782	rs7141608	0.51	0.9	0.9591
  hCV25942539	rs2401751	hCV30414828	rs7144432	0.51	0.9	0.9596
  hCV25942539	rs2401751	hCV32095396	rs11845147	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV32095401	rs11847417	0.51	0.9	0.9163
  hCV25942539	rs2401751	hCV32095402	rs11159857	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV32095403	rs4390529	0.51	0.9	0.917
  hCV25942539	rs2401751	hCV32095404	rs4301952	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV32095422	rs2033418	0.51	0.9	0.9135
  hCV25942539	rs2401751	hCV32095429	rs12436642	0.51	0.9	0.9381
  hCV25942539	rs2401751	hCV3211540	rs2274735	0.51	0.9	0.9793
  hCV25942539	rs2401751	hCV3211544	rs9323830	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV3211545	rs7160647	0.51	0.9	0.9163
  hCV25942539	rs2401751	hCV3211546	rs7143642	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV3211548	rs7151164	0.51	0.9	0.919
  hCV25942539	rs2401751	hCV3211561	rs8017811	0.51	0.9	0.9581
  hCV25942539	rs2401751	hCV3211562	rs4904454	0.51	0.9	0.9596
  hCV25942539	rs2401751	hCV3211566	rs930181	0.51	0.9	0.9591
  hCV25942539	rs2401751	hCV3211568	rs816075	0.51	0.9	1
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  hCV25942539	rs2401751	hCV9595849	rs1152376	0.51	0.9	0.9793
  hCV25942539	rs2401751	hCV9595856	rs816069	0.51	0.9	0.9586
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  hCV26000635	rs7020782	hCV31783431	rs6478232	0.51	0.9	0.959
  hCV26000635	rs7020782	hCV7594415	rs912214	0.51	0.9	0.9782
  hCV260164	rs6754295	hCV1026586	rs673548	0.51	0.9	0.9441
  hCV260164	rs6754295	hCV11168524	rs6544366	0.51	0.9	1
  hCV260164	rs6754295	hCV11168530	rs6728178	0.51	0.9	1
  hCV260164	rs6754295	hCV27912761	rs4564803	0.51	0.9	1
  hCV260164	rs6754295	hCV29011391	rs7557067	0.51	0.9	1
  hCV260164	rs6754295	hCV30455594	rs10184054	0.51	0.9	1
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  hCV260164	rs6754295	hCV3216558	rs676210	0.51	0.9	0.9442
  hCV260164	rs6754295	hCV7615376	rs1042034	0.51	0.9	0.9169
  hCV2632070	rs714052	hCV11449126	rs13244268	0.51	0.9	1
  hCV2632070	rs714052	hCV16164914	rs2074755	0.51	0.9	1
  hCV2632070	rs714052	hCV2632057	rs12056034	0.51	0.9	1
  hCV2632070	rs714052	hCV2632071	rs13231516	0.51	0.9	1
  hCV2632070	rs714052	hCV2632076	rs2240466	0.51	0.9	1
  hCV2632070	rs714052	hCV2632532	rs13246490	0.51	0.9	1
  hCV2632070	rs714052	hCV2632543	rs13232120	0.51	0.9	1
  hCV2632070	rs714052	hCV2632544	rs17145738	0.51	0.9	1
  hCV2632070	rs714052	hCV2632552	rs13233571	0.51	0.9	1
  hCV2632544	rs17145738	hCV11449126	rs13244268	0.51	0.9	1
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  hCV2632544	rs17145738	hCV2632071	rs13231516	0.51	0.9	1
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  hCV2632544	rs17145738	hCV2632532	rs13246490	0.51	0.9	1
  hCV2632544	rs17145738	hCV2632543	rs13232120	0.51	0.9	1
  hCV2632544	rs17145738	hCV2632552	rs13233571	0.51	0.9	1
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  hCV26660340	rs4968246	hCV11623006	rs1662596	0.51	0.681759041	0.743
  hCV26660340	rs4968246	hCV11623026	rs9911967	0.51	0.681759041	0.7492
  hCV26660340	rs4968246	hCV2275263	rs197912	0.51	0.681759041	0.71
  hCV26660340	rs4968246	hCV2275276	rs197925	0.51	0.681759041	0.7895
  hCV26660340	rs4968246	hCV2592646	rs12453279	0.51	0.681759041	0.917
  hCV26660340	rs4968246	hCV2592661	rs1867237	0.51	0.681759041	0.7492
  hCV26660340	rs4968246	hCV2592662	rs2191033	0.51	0.681759041	0.7264
  hCV26660340	rs4968246	hCV26660339	rs4968247	0.51	0.681759041	0.8732
  hCV26660340	rs4968246	hCV29195238	rs7225428	0.51	0.681759041	0.7492
  hCV26660340	rs4968246	hCV2959472	rs8078468	0.51	0.681759041	0.8732
  hCV26660340	rs4968246	hCV2960496	rs3760374	0.51	0.681759041	0.8791
  hCV26660340	rs4968246	hCV7451245	rs1662576	0.51	0.681759041	0.7492
  hCV26660340	rs4968246	hCV7451269	rs1662594	0.51	0.681759041	0.7492
  hCV26660340	rs4968246	hCV7451288	rs197911	0.51	0.681759041	0.756
  hCV26660340	rs4968246	hCV7451289	rs1056116	0.51	0.681759041	0.8732
  hCV26660340	rs4968246	hCV7451308	rs1638446	0.51	0.681759041	0.756
  hCV26683367	rs9894300	hCV11627552	rs2316667	0.51	0.60059725	0.9066
  hCV26683367	rs9894300	hCV1718966	rs4968305	0.51	0.60059725	0.9072
  hCV26683367	rs9894300	hCV26683368	rs2004580	0.51	0.60059725	0.8193
  hCV26683367	rs9894300	hCV29195269	rs7221042	0.51	0.60059725	0.6383
  hCV26683367	rs9894300	hCV30515746	rs10491149	0.51	0.60059725	0.6383
  hCV26683367	rs9894300	hCV31479380	rs4520895	0.51	0.60059725	0.8206
  hCV26683367	rs9894300	hDV70590478	rs9897338	0.51	0.60059725	0.8206
  hCV26683367	rs9894300	hDV70751669	rs16941353	0.51	0.60059725	0.6383
  hCV26683367	rs9894300	hDV70977122	rs17616652	0.51	0.60059725	0.6395
  hCV26683367	rs9894300	hDV70987720	rs17676978	0.51	0.60059725	0.6383
  hCV26683367	rs9894300	hDV75285090	rs2667804	0.51	0.60059725	0.9072
  hCV26683368	rs2004580	hCV11627552	rs2316667	0.51	0.600149065	0.8315
  hCV26683368	rs2004580	hCV1718966	rs4968305	0.51	0.600149065	0.9076
  hCV26683368	rs2004580	hCV26683367	rs9894300	0.51	0.600149065	0.8193
  hCV26683368	rs2004580	hCV31479380	rs4520895	0.51	0.600149065	0.8212
  hCV26683368	rs2004580	hDV70590478	rs9897338	0.51	0.600149065	0.8212
  hCV26683368	rs2004580	hDV70977122	rs17616652	0.51	0.600149065	0.6405
  hCV26683368	rs2004580	hDV75285090	rs2667804	0.51	0.600149065	0.9076
  hCV2741051	rs2230806	hCV15808302	rs2253182	0.51	0.9	1
  hCV2741051	rs2230806	hCV15808303	rs2253175	0.51	0.9	1
  hCV2741051	rs2230806	hCV15808304	rs2253172	0.51	0.9	1
  hCV2741051	rs2230806	hCV16235439	rs2472384	0.51	0.9	1
  hCV2741051	rs2230806	hCV16235449	rs2253174	0.51	0.9	1
  hCV2741051	rs2230806	hCV16235556	rs2253304	0.51	0.9	1
  hCV2741051	rs2230806	hCV16235566	rs2472439	0.51	0.9	0.9413
  hCV2741051	rs2230806	hCV2960435	rs2472433	0.51	0.9	0.9705
  hCV2741083	rs4149313	hCV2741071	rs7031748	0.51	0.9	0.9603
  hCV2741083	rs4149313	hCV2741079	rs4149310	0.51	0.9	1
  hCV2741083	rs4149313	hCV2741080	rs3780543	0.51	0.9	0.9603
  hCV2741083	rs4149313	hCV27979351	rs4149311	0.51	0.9	0.9603
  hCV2741083	rs4149313	hCV9306688	rs4743762	0.51	0.9	0.9603
  hCV27422538	rs6940254	hCV11226249	rs6415085	0.51	0.459494331	0.5362
  hCV27422538	rs6940254	hCV11285578	rs6926458	0.51	0.459494331	1
  hCV27422538	rs6940254	hCV11846435	rs6929299	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hCV1550866	rs6932014	0.51	0.459494331	0.5362
  hCV27422538	rs6940254	hCV243055	rs10945682	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hCV249895	rs7771129	0.51	0.459494331	0.5362
  hCV27422538	rs6940254	hCV249898	rs9456552	0.51	0.459494331	0.55
  hCV27422538	rs6940254	hCV25927459	rs3798221	0.51	0.459494331	0.6129
  hCV27422538	rs6940254	hCV26272388	rs7770685	0.51	0.459494331	1
  hCV27422538	rs6940254	hCV26272389	rs7760585	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hCV27422546	rs7761377	0.51	0.459494331	0.5504
  hCV27422538	rs6940254	hCV27422547	rs6455696	0.51	0.459494331	0.5336
  hCV27422538	rs6940254	hCV27422554	rs6923917	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hCV27422556	rs9355814	0.51	0.459494331	0.5659
  hCV27422538	rs6940254	hCV27422557	rs9355813	0.51	0.459494331	0.5875
  hCV27422538	rs6940254	hCV27422565	rs13202636	0.51	0.459494331	1
  hCV27422538	rs6940254	hCV29709361	rs9365179	0.51	0.459494331	0.5152
  hCV27422538	rs6940254	hCV29817515	rs9355817	0.51	0.459494331	0.51
  hCV27422538	rs6940254	hCV29934611	rs9295130	0.51	0.459494331	0.5291
  hCV27422538	rs6940254	hCV305046	rs6902102	0.51	0.459494331	0.5232
  hCV27422538	rs6940254	hCV31882494	rs12175867	0.51	0.459494331	1
  hCV27422538	rs6940254	hCV3201490	rs1321195	0.51	0.459494331	0.6
  hCV27422538	rs6940254	hCV3201495	rs1367210	0.51	0.459494331	0.6129
  hCV27422538	rs6940254	hCV3201497	rs1321196	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hCV8701273	rs783148	0.51	0.459494331	0.6
  hCV27422538	rs6940254	hCV8710154	rs1569933	0.51	0.459494331	0.5291
  hCV27422538	rs6940254	hCV8710161	rs1740428	0.51	0.459494331	0.5349
  hCV27422538	rs6940254	hDV77235995	rs7746273	0.51	0.459494331	0.5362
  hCV27462774	rs3127583	hCV16149755	rs2183470	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV16149755	rs2183470	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV27397381	rs3120149	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV27397381	rs3120149	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV27455194	rs3103347	0.51	0.708469605	0.9667
  hCV27462774	rs3127583	hCV27455194	rs3103347	0.51	0.756245335	0.9667
  hCV27462774	rs3127583	hCV27459536	rs3119310	0.51	0.708469605	0.776
  hCV27462774	rs3127583	hCV27459536	rs3119310	0.51	0.756245335	0.776
  hCV27462774	rs3127583	hCV27460663	rs3120137	0.51	0.708469605	0.9011
  hCV27462774	rs3127583	hCV27460663	rs3120137	0.51	0.756245335	0.9011
  hCV27462774	rs3127583	hCV27461119	rs3125056	0.51	0.708469605	0.8336
  hCV27462774	rs3127583	hCV27461119	rs3125056	0.51	0.756245335	0.8336
  hCV27462774	rs3127583	hCV27462007	rs3127578	0.51	0.708469605	0.776
  hCV27462774	rs3127583	hCV27462007	rs3127578	0.51	0.756245335	0.776
  hCV27462774	rs3127583	hCV27462671	rs3120139	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV27462671	rs3120139	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV27464241	rs3125052	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV27464241	rs3125052	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV27464790	rs3127591	0.51	0.708469605	0.9135
  hCV27462774	rs3127583	hCV27464790	rs3127591	0.51	0.756245335	0.9135
  hCV27462774	rs3127583	hCV30977815	rs3127597	0.51	0.708469605	0.8905
  hCV27462774	rs3127583	hCV30977815	rs3127597	0.51	0.756245335	0.8905
  hCV27462774	rs3127583	hCV30977817	rs3106168	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV30977817	rs3106168	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV30977839	rs3120140	0.51	0.708469605	0.8656
  hCV27462774	rs3127583	hCV30977839	rs3120140	0.51	0.756245335	0.8656
  hCV27462774	rs3127583	hCV30977855	rs3103350	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV30977855	rs3103350	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV31605072	rs12206585	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV31605072	rs12206585	0.51	0.756245335	1
  hCV27462774	rs3127583	hCV31605081	rs12203303	0.51	0.708469605	0.8994
  hCV27462774	rs3127583	hCV31605081	rs12203303	0.51	0.756245335	0.8994
  hCV27462774	rs3127583	hCV32312668	rs3103349	0.51	0.708469605	1
  hCV27462774	rs3127583	hCV32312668	rs3103349	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV71669191	rs3127586	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV71669191	rs3127586	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75428625	rs3106167	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV75428625	rs3106167	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75428626	rs3106170	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV75428626	rs3106170	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75428628	rs3106172	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV75428628	rs3106172	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75431938	rs3120151	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV75431938	rs3120151	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75433616	rs3125049	0.51	0.708469605	0.9278
  hCV27462774	rs3127583	hDV75433616	rs3125049	0.51	0.756245335	0.9278
  hCV27462774	rs3127583	hDV75433617	rs3125050	0.51	0.708469605	1
  hCV27462774	rs3127583	hDV75433617	rs3125050	0.51	0.756245335	1
  hCV27462774	rs3127583	hDV75433619	rs3125055	0.51	0.708469605	0.7337
  hCV27480853	rs3766430	hCV2431627	rs646534	0.51	0.9	0.9437
  hCV27480853	rs3766430	hCV27498227	rs3766431	0.51	0.9	0.9805
  hCV27480853	rs3766430	hCV27498228	rs3766436	0.51	0.9	0.9643
  hCV27480853	rs3766430	hCV27924561	rs4927080	0.51	0.9	0.9264
  hCV27480853	rs3766430	hCV29234422	rs3766437	0.51	0.9	0.9643
  hCV2762168	rs3939286	hCV12096527	rs1888909	0.51	0.9	0.9767
  hCV2762168	rs3939286	hCV12096531	rs928413	0.51	0.9	0.9767
  hCV2762168	rs3939286	hCV16108911	rs2095044	0.51	0.9	0.9616
  hCV2762168	rs3939286	hCV16225421	rs2381416	0.51	0.9	0.9252
  hCV2762168	rs3939286	hCV31940459	rs7848215	0.51	0.9	0.9252
  hCV2762168	rs3939286	hCV8785827	rs992969	0.51	0.9	1
  hCV2769554	rs1805010	hCV2769561	rs3024548	0.51	0.9	1
  hCV2769554	rs1805010	hCV2769568	rs3024530	0.51	0.9	0.926
  hCV2781953	rs6021931	hCV11182690	rs13045199	0.51	0.9	0.9391
  hCV2781953	rs6021931	hCV2487050	rs17806278	0.51	0.9	0.9391
  hCV2781953	rs6021931	hCV2487054	rs13043303	0.51	0.9	1
  hCV2781953	rs6021931	hCV2487070	rs6091546	0.51	0.9	1
  hCV2781953	rs6021931	hCV2487071	rs1473705	0.51	0.9	1
  hCV2781953	rs6021931	hCV2487073	rs17806379	0.51	0.9	0.9393
  hCV2781953	rs6021931	hCV2487087	rs13037630	0.51	0.9	1
  hCV2781953	rs6021931	hCV2516638	rs13037010	0.51	0.9	0.942
  hCV2781953	rs6021931	hCV2781950	rs6096949	0.51	0.9	1
  hCV2781953	rs6021931	hCV2781958	rs6096956	0.51	0.9	0.9694
  hCV2781953	rs6021931	hCV2781970	rs17806224	0.51	0.9	1
  hCV2781953	rs6021931	hCV31734434	rs13039375	0.51	0.9	1
  hCV2781953	rs6021931	hCV31734442	rs13039956	0.51	0.9	1
  hCV2781953	rs6021931	hDV71605793	rs17203653	0.51	0.9	1
  hCV27884601	rs4908776	hCV1188731	rs4908514	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV1188735	rs10864366	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV27157507	rs6664000	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV27157524	rs6577531	0.51	0.900202572	0.9351
  hCV27884601	rs4908776	hCV28023091	rs4908773	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV29368919	rs4908513	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV29873524	rs7533113	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV29945430	rs7517436	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV30035535	rs7518204	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV32055527	rs10864364	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV32055579	rs6577522	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV32055595	rs6577524	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV32055596	rs6577525	0.51	0.900202572	1
  hCV27884601	rs4908776	hCV32055637	rs6577532	0.51	0.900202572	0.9312
  hCV27884601	rs4908776	hCV8823713	rs1472228	0.51	0.900202572	1
  hCV27958354	rs4908762	hCV29873526	rs6697997	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV3086998	rs7530863	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV3087000	rs1463055	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV3087003	rs6577500	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV3087015	rs11121198	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV32055548	rs11121197	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV32055677	rs10864355	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV529178	rs301811	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV597227	rs301809	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV597229	rs301785	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV8824288	rs910582	0.51	0.969446018	1
  hCV27958354	rs4908762	hCV8881161	rs926951	0.51	0.969446018	1
  hCV28008078	rs4745543	hCV11765753	rs3793456	0.51	0.766415386	0.8388
  hCV28008078	rs4745543	hCV1463112	rs3763608	0.51	0.766415386	1
  hCV28008078	rs4745543	hCV1463244	rs3793465	0.51	0.766415386	0.827
  hCV28008078	rs4745543	hCV1463252	rs3793461	0.51	0.766415386	0.8689
  hCV28008078	rs4745543	hCV15761059	rs2309393	0.51	0.766415386	0.827
  hCV28008078	rs4745543	hCV26566199	rs3793467	0.51	0.766415386	0.8689
  hCV28008078	rs4745543	hCV30586985	rs10126006	0.51	0.766415386	0.8573
  hCV28008078	rs4745543	hCV31363797	rs11145043	0.51	0.766415386	0.792
  hCV28008078	rs4745543	hCV31363840	rs7875693	0.51	0.766415386	0.7884
  hCV28008078	rs4745543	hCV31363841	rs7849347	0.51	0.766415386	0.8065
  hCV28008078	rs4745543	hCV31363984	rs7855905	0.51	0.766415386	0.792
  hCV28023091	rs4908773	hCV11398434	rs1812457	0.51	0.495466362	0.7979
  hCV28023091	rs4908773	hCV11398437	rs1817367	0.51	0.495466362	0.6548
  hCV28023091	rs4908773	hCV11675962	rs10746481	0.51	0.495466362	0.8704
  hCV28023091	rs4908773	hCV1188659	rs3820037	0.51	0.495466362	0.5447
  hCV28023091	rs4908773	hCV1188660	rs6660137	0.51	0.495466362	0.5538
  hCV28023091	rs4908773	hCV1188664	rs2765511	0.51	0.495466362	0.6126
  hCV28023091	rs4908773	hCV1188665	rs2781060	0.51	0.495466362	0.6354
  hCV28023091	rs4908773	hCV1188676	rs11121247	0.51	0.495466362	0.5538
  hCV28023091	rs4908773	hCV1188731	rs4908514	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV1188735	rs10864366	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV12040675	rs2038904	0.51	0.495466362	0.6126
  hCV28023091	rs4908773	hCV15882429	rs2289732	0.51	0.495466362	0.6247
  hCV28023091	rs4908773	hCV15932991	rs2781067	0.51	0.495466362	0.6188
  hCV28023091	rs4908773	hCV15932992	rs2781068	0.51	0.495466362	0.6121
  hCV28023091	rs4908773	hCV27157507	rs6664000	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV27157524	rs6577531	0.51	0.495466362	0.9314
  hCV28023091	rs4908773	hCV2741759	rs11121179	0.51	0.495466362	0.6713
  hCV28023091	rs4908773	hCV27474399	rs3753275	0.51	0.495466362	0.5807
  hCV28023091	rs4908773	hCV27884601	rs4908776	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV27958354	rs4908762	0.51	0.495466362	0.6717
  hCV28023091	rs4908773	hCV29368919	rs4908513	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV2943451	rs902355	0.51	0.495466362	0.7098
  hCV28023091	rs4908773	hCV2943853	rs301793	0.51	0.495466362	0.6247
  hCV28023091	rs4908773	hCV2966436	rs11121174	0.51	0.495466362	0.6247
  hCV28023091	rs4908773	hCV2966437	rs11580417	0.51	0.495466362	0.6247
  hCV28023091	rs4908773	hCV2966441	rs6684863	0.51	0.495466362	0.6247
  hCV28023091	rs4908773	hCV2966444	rs11121171	0.51	0.495466362	0.6727
  hCV28023091	rs4908773	hCV29819064	rs6698079	0.51	0.495466362	0.7458
  hCV28023091	rs4908773	hCV2987250	rs301810	0.51	0.495466362	0.5105
  hCV28023091	rs4908773	hCV29873524	rs7533113	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV29873526	rs6697997	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV29945430	rs7517436	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV30035535	rs7518204	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV30125699	rs4581300	0.51	0.495466362	0.6067
  hCV28023091	rs4908773	hCV30143725	rs6690050	0.51	0.495466362	0.7437
  hCV28023091	rs4908773	hCV30467730	rs6702457	0.51	0.495466362	0.8704
  hCV28023091	rs4908773	hCV3086930	rs6658881	0.51	0.495466362	0.8213
  hCV28023091	rs4908773	hCV3086932	rs7533442	0.51	0.495466362	0.8213
  hCV28023091	rs4908773	hCV3086950	rs4908771	0.51	0.495466362	0.8704
  hCV28023091	rs4908773	hCV3086961	rs6703577	0.51	0.495466362	0.7188
  hCV28023091	rs4908773	hCV3086971	rs6679948	0.51	0.495466362	0.7979
  hCV28023091	rs4908773	hCV3086972	rs6688329	0.51	0.495466362	0.8568
  hCV28023091	rs4908773	hCV3086998	rs7530863	0.51	0.495466362	0.6717
  hCV28023091	rs4908773	hCV3087000	rs1463055	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV3087003	rs6577500	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV3087015	rs11121198	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV3087016	rs2297867	0.51	0.495466362	0.6499
  hCV28023091	rs4908773	hCV32055284	rs12079653	0.51	0.495466362	0.6676
  hCV28023091	rs4908773	hCV32055470	rs6577506	0.51	0.495466362	0.7188
  hCV28023091	rs4908773	hCV32055474	rs10864359	0.51	0.495466362	0.6717
  hCV28023091	rs4908773	hCV32055477	rs10779705	0.51	0.495466362	0.7979
  hCV28023091	rs4908773	hCV32055527	rs10864364	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV32055548	rs11121197	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV32055579	rs6577522	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV32055595	rs6577524	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV32055596	rs6577525	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV32055625	rs6678590	0.51	0.495466362	0.8645
  hCV28023091	rs4908773	hCV32055637	rs6577532	0.51	0.495466362	0.8301
  hCV28023091	rs4908773	hCV32055662	rs6677249	0.51	0.495466362	0.645
  hCV28023091	rs4908773	hCV32055677	rs10864355	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV529178	rs301811	0.51	0.495466362	0.6949
  hCV28023091	rs4908773	hCV529182	rs301800	0.51	0.495466362	0.6998
  hCV28023091	rs4908773	hCV597227	rs301809	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV597229	rs301785	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV877241	rs301788	0.51	0.495466362	0.6713
  hCV28023091	rs4908773	hCV8823713	rs1472228	0.51	0.495466362	1
  hCV28023091	rs4908773	hCV8824244	rs1006950	0.51	0.495466362	0.574
  hCV28023091	rs4908773	hCV8824248	rs1543711	0.51	0.495466362	0.6126
  hCV28023091	rs4908773	hCV8824288	rs910582	0.51	0.495466362	0.6952
  hCV28023091	rs4908773	hCV8824394	rs1443929	0.51	0.495466362	0.6713
  hCV28023091	rs4908773	hCV8824424	rs1058790	0.51	0.495466362	0.6727
  hCV28023091	rs4908773	hCV8824425	rs1058791	0.51	0.495466362	0.6383
  hCV28023091	rs4908773	hCV8881145	rs1038008	0.51	0.495466362	0.7979
  hCV28023091	rs4908773	hCV8881146	rs1463054	0.51	0.495466362	0.8032
  hCV28023091	rs4908773	hCV8881157	rs1535158	0.51	0.495466362	0.7979
  hCV28023091	rs4908773	hCV8881161	rs926951	0.51	0.495466362	0.6717
  hCV282793	rs11751605	hCV30977815	rs3127597	0.51	0.782580889	0.801
  hCV28960526	rs6853079	hCV28960525	rs6532740	0.51	0.9	1
  hCV28960526	rs6853079	hCV29480044	rs10516433	0.51	0.9	1
  hCV28960526	rs6853079	hCV30454150	rs10516434	0.51	0.9	0.9309
  hCV28960526	rs6853079	hCV30694936	rs6840610	0.51	0.9	1
  hCV28960526	rs6853079	hDV70961198	rs17498778	0.51	0.9	1
  hCV28960526	rs6853079	hDV70961229	rs17499015	0.51	0.9	0.9398
  hCV28960526	rs6853079	hDV70969482	rs17564872	0.51	0.9	1
  hCV28960526	rs6853079	hDV71951446	rs7689289	0.51	0.9	1
  hCV28974083	rs8032553	hCV26066881	rs11629584	0.51	0.9	1
  hCV28974083	rs8032553	hCV30732106	rs4556765	0.51	0.9	0.9647
  hCV28974083	rs8032553	hCV31590435	rs11634571	0.51	0.9	0.9634
  hCV29011391	rs7557067	hCV11168524	rs6544366	0.51	0.9	1
  hCV29011391	rs7557067	hCV11168530	rs6728178	0.51	0.9	1
  hCV29011391	rs7557067	hCV260164	rs6754295	0.51	0.9	1
  hCV29011391	rs7557067	hCV27912761	rs4564803	0.51	0.9	1
  hCV29011391	rs7557067	hCV30455594	rs10184054	0.51	0.9	1
  hCV29011391	rs7557067	hCV30847428	rs11902417	0.51	0.9	1
  hCV29135108	rs6743779	hCV2772191	rs10170608	0.51	0.9	0.9005
  hCV2932115	rs5517	hCV1531092	rs3745522	0.51	0.9	0.9476
  hCV2932115	rs5517	hCV29188580	rs3212820	0.51	0.9	1
  hCV2932115	rs5517	hCV2932116	rs5519	0.51	0.9	1
  hCV29322781	rs6921516	hCV103951	rs6455688	0.51	0.465336662	0.9792
  hCV29322781	rs6921516	hCV103951	rs6455688	0.51	0.622712349	0.9792
  hCV29322781	rs6921516	hCV103952	rs6923877	0.51	0.465336662	0.9792
  hCV29322781	rs6921516	hCV103952	rs6923877	0.51	0.622712349	0.9792
  hCV29322781	rs6921516	hCV11226249	rs6415085	0.51	0.465336662	0.7601
  hCV29322781	rs6921516	hCV11226249	rs6415085	0.51	0.622712349	0.7601
  hCV29322781	rs6921516	hCV11284288	rs9457946	0.51	0.465336662	1
  hCV29322781	rs6921516	hCV11284288	rs9457946	0.51	0.622712349	1
  hCV29322781	rs6921516	hCV11846435	rs6929299	0.51	0.465336662	0.8326
  hCV29322781	rs6921516	hCV11846435	rs6929299	0.51	0.622712349	0.8326
  hCV29322781	rs6921516	hCV1550866	rs6932014	0.51	0.465336662	0.7601
  hCV29322781	rs6921516	hCV1550866	rs6932014	0.51	0.622712349	0.7601
  hCV29322781	rs6921516	hCV1550871	rs9355295	0.51	0.465336662	1
  hCV29322781	rs6921516	hCV1550871	rs9355295	0.51	0.622712349	1
  hCV29322781	rs6921516	hCV207123	rs7771801	0.51	0.465336662	1
  hCV29322781	rs6921516	hCV207123	rs7771801	0.51	0.622712349	1
  hCV29322781	rs6921516	hCV207127	rs7453899	0.51	0.465336662	0.9795
  hCV29322781	rs6921516	hCV207127	rs7453899	0.51	0.622712349	0.9795
  hCV29322781	rs6921516	hCV207128	rs6455689	0.51	0.465336662	0.9184
  hCV29322781	rs6921516	hCV207128	rs6455689	0.51	0.622712349	0.9184
  hCV29322781	rs6921516	hCV243055	rs10945682	0.51	0.465336662	0.8334
  hCV29322781	rs6921516	hCV243055	rs10945682	0.51	0.622712349	0.8334
  hCV29322781	rs6921516	hCV249895	rs7771129	0.51	0.465336662	0.7601
  hCV29322781	rs6921516	hCV249895	rs7771129	0.51	0.622712349	0.7601
  hCV29322781	rs6921516	hCV249897	rs6913833	0.51	0.465336662	0.6796
  hCV29322781	rs6921516	hCV249897	rs6913833	0.51	0.622712349	0.6796
  hCV29322781	rs6921516	hCV249898	rs9456552	0.51	0.465336662	0.7704
  hCV29322781	rs6921516	hCV249898	rs9456552	0.51	0.622712349	0.7704
  hCV29322781	rs6921516	hCV25929408	rs7765781	0.51	0.465336662	1
  hCV29322781	rs6921516	hCV25929408	rs7765781	0.51	0.622712349	1
  hCV29322781	rs6921516	hCV25929478	rs7765803	0.51	0.465336662	0.9795
  hCV29322781	rs6921516	hCV25929478	rs7765803	0.51	0.622712349	0.9795
  hCV29322781	rs6921516	hCV26272389	rs7760585	0.51	0.465336662	0.8334
  hCV29322781	rs6921516	hCV26272389	rs7760585	0.51	0.622712349	0.8334
  hCV29322781	rs6921516	hCV27422546	rs7761377	0.51	0.465336662	0.722
  hCV29322781	rs6921516	hCV27422546	rs7761377	0.51	0.622712349	0.722
  hCV29322781	rs6921516	hCV27422547	rs6455696	0.51	0.465336662	0.7271
  hCV29322781	rs6921516	hCV27422547	rs6455696	0.51	0.622712349	0.7271
  hCV29322781	rs6921516	hCV27422554	rs6923917	0.51	0.465336662	0.8334
  hCV29322781	rs6921516	hCV27422554	rs6923917	0.51	0.622712349	0.8334
  hCV29322781	rs6921516	hCV27422556	rs9355814	0.51	0.465336662	0.7413
  hCV29322781	rs6921516	hCV27422556	rs9355814	0.51	0.622712349	0.7413
  hCV29322781	rs6921516	hCV27422557	rs9355813	0.51	0.465336662	0.767
  hCV29322781	rs6921516	hCV27422557	rs9355813	0.51	0.622712349	0.767
  hCV29322781	rs6921516	hCV27422575	rs6415084	0.51	0.465336662	0.4788
  hCV29322781	rs6921516	hCV29546641	rs9365171	0.51	0.465336662	0.8819
  hCV29322781	rs6921516	hCV29546641	rs9365171	0.51	0.622712349	0.8819
  hCV29322781	rs6921516	hCV29709361	rs9365179	0.51	0.465336662	0.8171
  hCV29322781	rs6921516	hCV29709361	rs9365179	0.51	0.622712349	0.8171
  hCV29322781	rs6921516	hCV29817515	rs9355817	0.51	0.465336662	0.6883
  hCV29322781	rs6921516	hCV29817515	rs9355817	0.51	0.622712349	0.6883
  hCV29322781	rs6921516	hCV29934611	rs9295130	0.51	0.465336662	0.8152
  hCV29322781	rs6921516	hCV29934611	rs9295130	0.51	0.622712349	0.8152
  hCV29322781	rs6921516	hCV29998162	rs9457943	0.51	0.465336662	1
  hCV29322781	rs6921516	hCV29998162	rs9457943	0.51	0.622712349	1
  hCV29322781	rs6921516	hCV305046	rs6902102	0.51	0.465336662	0.7529
  hCV29322781	rs6921516	hCV305046	rs6902102	0.51	0.622712349	0.7529
  hCV29322781	rs6921516	hCV30574599	rs7770628	0.51	0.465336662	0.4698
  hCV29322781	rs6921516	hCV3201494	rs1367209	0.51	0.465336662	0.7291
  hCV29322781	rs6921516	hCV3201494	rs1367209	0.51	0.622712349	0.7291
  hCV29322781	rs6921516	hCV3201497	rs1321196	0.51	0.465336662	0.8334
  hCV29322781	rs6921516	hCV3201497	rs1321196	0.51	0.622712349	0.8334
  hCV29322781	rs6921516	hCV8710154	rs1569933	0.51	0.465336662	0.8274
  hCV29322781	rs6921516	hCV8710154	rs1569933	0.51	0.622712349	0.8274
  hCV29322781	rs6921516	hCV8710161	rs1740428	0.51	0.465336662	0.8334
  hCV29322781	rs6921516	hCV8710161	rs1740428	0.51	0.622712349	0.8334
  hCV29322781	rs6921516	hCV8710162	rs1367211	0.51	0.465336662	0.7291
  hCV29322781	rs6921516	hCV8710162	rs1367211	0.51	0.622712349	0.7291
  hCV29322781	rs6921516	hDV77235995	rs7746273	0.51	0.465336662	0.6915
  hCV29322781	rs6921516	hDV77235995	rs7746273	0.51	0.622712349	0.6915
  hCV29368919	rs4908513	hCV11398434	rs1812457	0.51	0.496733059	0.8094
  hCV29368919	rs4908513	hCV11398437	rs1817367	0.51	0.496733059	0.7755
  hCV29368919	rs4908513	hCV11675962	rs10746481	0.51	0.496733059	0.8774
  hCV29368919	rs4908513	hCV1188659	rs3820037	0.51	0.496733059	0.5968
  hCV29368919	rs4908513	hCV1188660	rs6660137	0.51	0.496733059	0.6126
  hCV29368919	rs4908513	hCV1188664	rs2765511	0.51	0.496733059	0.6312
  hCV29368919	rs4908513	hCV1188665	rs2781060	0.51	0.496733059	0.6541
  hCV29368919	rs4908513	hCV1188676	rs11121247	0.51	0.496733059	0.6126
  hCV29368919	rs4908513	hCV1188731	rs4908514	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV1188735	rs10864366	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV12040675	rs2038904	0.51	0.496733059	0.6312
  hCV29368919	rs4908513	hCV15882429	rs2289732	0.51	0.496733059	0.6452
  hCV29368919	rs4908513	hCV15932991	rs2781067	0.51	0.496733059	0.6396
  hCV29368919	rs4908513	hCV15932992	rs2781068	0.51	0.496733059	0.6308
  hCV29368919	rs4908513	hCV27157507	rs6664000	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV27157524	rs6577531	0.51	0.496733059	0.9353
  hCV29368919	rs4908513	hCV27157546	rs11811795	0.51	0.496733059	0.5453
  hCV29368919	rs4908513	hCV27157560	rs11121252	0.51	0.496733059	0.5135
  hCV29368919	rs4908513	hCV2741759	rs11121179	0.51	0.496733059	0.6247
  hCV29368919	rs4908513	hCV27884601	rs4908776	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV27958354	rs4908762	0.51	0.496733059	0.6952
  hCV29368919	rs4908513	hCV28023091	rs4908773	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV2943451	rs902355	0.51	0.496733059	0.7273
  hCV29368919	rs4908513	hCV2943853	rs301793	0.51	0.496733059	0.6452
  hCV29368919	rs4908513	hCV2966436	rs11121174	0.51	0.496733059	0.6452
  hCV29368919	rs4908513	hCV2966437	rs11580417	0.51	0.496733059	0.6452
  hCV29368919	rs4908513	hCV2966441	rs6684863	0.51	0.496733059	0.6452
  hCV29368919	rs4908513	hCV2966444	rs11121171	0.51	0.496733059	0.6911
  hCV29368919	rs4908513	hCV29819064	rs6698079	0.51	0.496733059	0.7479
  hCV29368919	rs4908513	hCV2987250	rs301810	0.51	0.496733059	0.5341
  hCV29368919	rs4908513	hCV29873524	rs7533113	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV29873526	rs6697997	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV29945430	rs7517436	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV30035535	rs7518204	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV30125699	rs4581300	0.51	0.496733059	0.6952
  hCV29368919	rs4908513	hCV30143725	rs6690050	0.51	0.496733059	0.7577
  hCV29368919	rs4908513	hCV30467730	rs6702457	0.51	0.496733059	0.8774
  hCV29368919	rs4908513	hCV3086930	rs6658881	0.51	0.496733059	0.8704
  hCV29368919	rs4908513	hCV3086932	rs7533442	0.51	0.496733059	0.8704
  hCV29368919	rs4908513	hCV3086950	rs4908771	0.51	0.496733059	0.8774
  hCV29368919	rs4908513	hCV3086961	rs6703577	0.51	0.496733059	0.7979
  hCV29368919	rs4908513	hCV3086971	rs6679948	0.51	0.496733059	0.8094
  hCV29368919	rs4908513	hCV3086972	rs6688329	0.51	0.496733059	0.8654
  hCV29368919	rs4908513	hCV3086998	rs7530863	0.51	0.496733059	0.6952
  hCV29368919	rs4908513	hCV3087000	rs1463055	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV3087003	rs6577500	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV3087015	rs11121198	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV3087016	rs2297867	0.51	0.496733059	0.6952
  hCV29368919	rs4908513	hCV32055284	rs12079653	0.51	0.496733059	0.6858
  hCV29368919	rs4908513	hCV32055470	rs6577506	0.51	0.496733059	0.7979
  hCV29368919	rs4908513	hCV32055474	rs10864359	0.51	0.496733059	0.7979
  hCV29368919	rs4908513	hCV32055477	rs10779705	0.51	0.496733059	0.8094
  hCV29368919	rs4908513	hCV32055527	rs10864364	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV32055548	rs11121197	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV32055579	rs6577522	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV32055595	rs6577524	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV32055596	rs6577525	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV32055625	rs6678590	0.51	0.496733059	0.879
  hCV29368919	rs4908513	hCV32055637	rs6577532	0.51	0.496733059	0.9314
  hCV29368919	rs4908513	hCV32055662	rs6677249	0.51	0.496733059	0.7437
  hCV29368919	rs4908513	hCV32055677	rs10864355	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV529178	rs301811	0.51	0.496733059	0.7109
  hCV29368919	rs4908513	hCV529182	rs301800	0.51	0.496733059	0.6732
  hCV29368919	rs4908513	hCV597227	rs301809	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV597229	rs301785	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV877241	rs301788	0.51	0.496733059	0.6247
  hCV29368919	rs4908513	hCV8823713	rs1472228	0.51	0.496733059	1
  hCV29368919	rs4908513	hCV8824241	rs1325920	0.51	0.496733059	0.5423
  hCV29368919	rs4908513	hCV8824244	rs1006950	0.51	0.496733059	0.6126
  hCV29368919	rs4908513	hCV8824248	rs1543711	0.51	0.496733059	0.6312
  hCV29368919	rs4908513	hCV8824288	rs910582	0.51	0.496733059	0.7112
  hCV29368919	rs4908513	hCV8824394	rs1443929	0.51	0.496733059	0.6247
  hCV29368919	rs4908513	hCV8824424	rs1058790	0.51	0.496733059	0.6911
  hCV29368919	rs4908513	hCV8824425	rs1058791	0.51	0.496733059	0.6721
  hCV29368919	rs4908513	hCV8881145	rs1038008	0.51	0.496733059	0.8094
  hCV29368919	rs4908513	hCV8881146	rs1463054	0.51	0.496733059	0.8042
  hCV29368919	rs4908513	hCV8881157	rs1535158	0.51	0.496733059	0.8094
  hCV29368919	rs4908513	hCV8881161	rs926951	0.51	0.496733059	0.6952
  hCV29480044	rs10516433	hCV28960525	rs6532740	0.51	0.9	1
  hCV29480044	rs10516433	hCV28960526	rs6853079	0.51	0.9	1
  hCV29480044	rs10516433	hCV30454150	rs10516434	0.51	0.9	0.9309
  hCV29480044	rs10516433	hCV30694936	rs6840610	0.51	0.9	1
  hCV29480044	rs10516433	hDV70961198	rs17498778	0.51	0.9	1
  hCV29480044	rs10516433	hDV70961229	rs17499015	0.51	0.9	0.9398
  hCV29480044	rs10516433	hDV70969482	rs17564872	0.51	0.9	1
  hCV29480044	rs10516433	hDV71951446	rs7689289	0.51	0.9	1
  hCV2960489	rs3785889	hCV10293	rs3851786	0.51	0.784117293	0.8104
  hCV2960489	rs3785889	hCV11623025	rs9898981	0.51	0.784117293	0.8121
  hCV2960489	rs3785889	hCV11623029	rs2316330	0.51	0.784117293	0.8195
  hCV2960489	rs3785889	hCV2275283	rs740617	0.51	0.784117293	0.7937
  hCV2960489	rs3785889	hCV2592671	rs197926	0.51	0.784117293	0.8209
  hCV2960489	rs3785889	hCV2592673	rs4968286	0.51	0.784117293	0.8591
  hCV2960489	rs3785889	hCV2592677	rs736604	0.51	0.784117293	0.8209
  hCV2960489	rs3785889	hCV2592681	rs17608961	0.51	0.784117293	0.8586
  hCV2960489	rs3785889	hCV26660327	rs11869840	0.51	0.784117293	0.8578
  hCV2960489	rs3785889	hCV29195266	rs3809854	0.51	0.784117293	0.8209
  hCV2960489	rs3785889	hCV2959464	rs3760377	0.51	0.784117293	0.8591
  hCV2960489	rs3785889	hCV2959466	rs6504622	0.51	0.784117293	0.8591
  hCV2960489	rs3785889	hCV30299603	rs9889762	0.51	0.784117293	0.8398
  hCV2960489	rs3785889	hCV31466218	rs11079745	0.51	0.784117293	0.8586
  hCV2960489	rs3785889	hCV31466219	rs11652318	0.51	0.784117293	0.8195
  hCV2960489	rs3785889	hCV7448063	rs736603	0.51	0.784117293	0.816
  hCV2960489	rs3785889	hCV7451199	rs3851785	0.51	0.784117293	0.8195
  hCV2960489	rs3785889	hCV7451217	rs1052586	0.51	0.784117293	0.8398
  hCV29684678	rs10486788	hCV11811746	rs12669397	0.51	0.9	0.9583
  hCV29684678	rs10486788	hCV2641110	rs6948282	0.51	0.9	0.9783
  hCV29684678	rs10486788	hCV2641111	rs13239842	0.51	0.9	0.9783
  hCV29684678	rs10486788	hCV2641141	rs13236237	0.51	0.9	0.9583
  hCV29684678	rs10486788	hCV2641147	rs13234986	0.51	0.9	1
  hCV29684678	rs10486788	hCV2641150	rs17169192	0.51	0.9	1
  hCV29684678	rs10486788	hCV26518087	rs12699759	0.51	0.9	0.9783
  hCV29684678	rs10486788	hCV31310415	rs12674430	0.51	0.9	1
  hCV29684678	rs10486788	hCV31310435	rs10950592	0.51	0.9	0.9184
  hCV29684678	rs10486788	hCV31310483	rs13230922	0.51	0.9	0.919
  hCV29684678	rs10486788	hCV7603468	rs1299916	0.51	0.9	1
  hCV29684678	rs10486788	hDV70913803	rs17169201	0.51	0.9	1
  hCV29819064	rs6698079	hCV11398434	rs1812457	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV11398437	rs1817367	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV11675962	rs10746481	0.51	0.900593335	0.919
  hCV29819064	rs6698079	hCV30143725	rs6690050	0.51	0.900593335	0.919
  hCV29819064	rs6698079	hCV30467730	rs6702457	0.51	0.900593335	0.919
  hCV29819064	rs6698079	hCV3086930	rs6658881	0.51	0.900593335	0.9184
  hCV29819064	rs6698079	hCV3086932	rs7533442	0.51	0.900593335	0.9184
  hCV29819064	rs6698079	hCV3086950	rs4908771	0.51	0.900593335	0.919
  hCV29819064	rs6698079	hCV3086961	rs6703577	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV3086971	rs6679948	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV3086972	rs6688329	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV32055470	rs6577506	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV32055474	rs10864359	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV32055477	rs10779705	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV8881145	rs1038008	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV8881146	rs1463054	0.51	0.900593335	1
  hCV29819064	rs6698079	hCV8881157	rs1535158	0.51	0.900593335	1
  hCV2983035	rs9527026	hCV25611075	rs7997728	0.51	0.9	1
  hCV2983035	rs9527026	hCV29426416	rs8000084	0.51	0.9	1
  hCV2983035	rs9527026	hCV29426417	rs8001148	0.51	0.9	1
  hCV2983035	rs9527026	hCV29426429	rs7986435	0.51	0.9	1
  hCV2983035	rs9527026	hCV29676871	rs9527032	0.51	0.9	0.9428
  hCV2983035	rs9527026	hCV29803144	rs7982726	0.51	0.9	1
  hCV2983035	rs9527026	hCV2983036	rs9527025	0.51	0.9	1
  hCV2983035	rs9527026	hCV2983037	rs9536314	0.51	0.9	1
  hCV2983035	rs9527026	hCV2983038	rs9536313	0.51	0.9	1
  hCV2983035	rs9527026	hCV2983040	rs9527024	0.51	0.9	1
  hCV2983035	rs9527026	hCV29929821	rs9536239	0.51	0.9	1
  hCV2983035	rs9527026	hCV30109848	rs9526990	0.51	0.9	1
  hCV2983035	rs9527026	hCV30181994	rs9527022	0.51	0.9	1
  hCV2983035	rs9527026	hCV30217619	rs9527023	0.51	0.9	1
  hCV2983035	rs9527026	hCV30452057	rs9526992	0.51	0.9	0.9174
  hCV2983035	rs9527026	hCV30469913	rs9536234	0.51	0.9	1
  hCV2983035	rs9527026	hCV30487772	rs9526998	0.51	0.9	1
  hCV2983035	rs9527026	hCV30560346	rs9527021	0.51	0.9	1
  hCV2983035	rs9527026	hCV32231920	rs12020187	0.51	0.9	1
  hCV2983035	rs9527026	hDV72067820	rs9536282	0.51	0.9	0.9674
  hCV2983036	rs9527025	hCV25611075	rs7997728	0.51	0.9	1
  hCV2983036	rs9527025	hCV29426416	rs8000084	0.51	0.9	1
  hCV2983036	rs9527025	hCV29426417	rs8001148	0.51	0.9	1
  hCV2983036	rs9527025	hCV29426429	rs7986435	0.51	0.9	1
  hCV2983036	rs9527025	hCV29676871	rs9527032	0.51	0.9	0.9438
  hCV2983036	rs9527025	hCV29803144	rs7982726	0.51	0.9	1
  hCV2983036	rs9527025	hCV2983035	rs9527026	0.51	0.9	1
  hCV2983036	rs9527025	hCV2983037	rs9536314	0.51	0.9	1
  hCV2983036	rs9527025	hCV2983038	rs9536313	0.51	0.9	1
  hCV2983036	rs9527025	hCV2983040	rs9527024	0.51	0.9	1
  hCV2983036	rs9527025	hCV29929821	rs9536239	0.51	0.9	1
  hCV2983036	rs9527025	hCV30109848	rs9526990	0.51	0.9	1
  hCV2983036	rs9527025	hCV30181994	rs9527022	0.51	0.9	1
  hCV2983036	rs9527025	hCV30217619	rs9527023	0.51	0.9	1
  hCV2983036	rs9527025	hCV30452057	rs9526992	0.51	0.9	0.9184
  hCV2983036	rs9527025	hCV30469913	rs9536234	0.51	0.9	1
  hCV2983036	rs9527025	hCV30487772	rs9526998	0.51	0.9	1
  hCV2983036	rs9527025	hCV30560346	rs9527021	0.51	0.9	1
  hCV2983036	rs9527025	hCV32231920	rs12020187	0.51	0.9	1
  hCV2983036	rs9527025	hDV72067820	rs9536282	0.51	0.9	0.9438
  hCV2987250	rs301810	hCV11398434	rs1812457	0.51	0.515143538	0.7861
  hCV2987250	rs301810	hCV11398437	rs1817367	0.51	0.515143538	0.7562
  hCV2987250	rs301810	hCV11675962	rs10746481	0.51	0.515143538	0.7323
  hCV2987250	rs301810	hCV1188731	rs4908514	0.51	0.515143538	0.6312
  hCV2987250	rs301810	hCV15882429	rs2289732	0.51	0.515143538	0.6324
  hCV2987250	rs301810	hCV27157507	rs6664000	0.51	0.515143538	0.6126
  hCV2987250	rs301810	hCV2741759	rs11121179	0.51	0.515143538	0.5153
  hCV2987250	rs301810	hCV27884601	rs4908776	0.51	0.515143538	0.5328
  hCV2987250	rs301810	hCV27958354	rs4908762	0.51	0.515143538	0.8853
  hCV2987250	rs301810	hCV29368919	rs4908513	0.51	0.515143538	0.5341
  hCV2987250	rs301810	hCV2943451	rs902355	0.51	0.515143538	0.6527
  hCV2987250	rs301810	hCV2943853	rs301793	0.51	0.515143538	0.5389
  hCV2987250	rs301810	hCV2966436	rs11121174	0.51	0.515143538	0.5389
  hCV2987250	rs301810	hCV2966437	rs11580417	0.51	0.515143538	0.6324
  hCV2987250	rs301810	hCV2966441	rs6684863	0.51	0.515143538	0.6324
  hCV2987250	rs301810	hCV2966444	rs11121171	0.51	0.515143538	0.6809
  hCV2987250	rs301810	hCV29819064	rs6698079	0.51	0.515143538	0.7332
  hCV2987250	rs301810	hCV29873524	rs7533113	0.51	0.515143538	0.6312
  hCV2987250	rs301810	hCV29873526	rs6697997	0.51	0.515143538	0.8909
  hCV2987250	rs301810	hCV29945430	rs7517436	0.51	0.515143538	0.6126
  hCV2987250	rs301810	hCV30035535	rs7518204	0.51	0.515143538	0.5318
  hCV2987250	rs301810	hCV30125699	rs4581300	0.51	0.515143538	0.7731
  hCV2987250	rs301810	hCV30143725	rs6690050	0.51	0.515143538	0.7323
  hCV2987250	rs301810	hCV30467730	rs6702457	0.51	0.515143538	0.633
  hCV2987250	rs301810	hCV3086930	rs6658881	0.51	0.515143538	0.7185
  hCV2987250	rs301810	hCV3086932	rs7533442	0.51	0.515143538	0.7185
  hCV2987250	rs301810	hCV3086950	rs4908771	0.51	0.515143538	0.7323
  hCV2987250	rs301810	hCV3086961	rs6703577	0.51	0.515143538	0.665
  hCV2987250	rs301810	hCV3086971	rs6679948	0.51	0.515143538	0.6812
  hCV2987250	rs301810	hCV3086972	rs6688329	0.51	0.515143538	0.7073
  hCV2987250	rs301810	hCV3086998	rs7530863	0.51	0.515143538	0.8853
  hCV2987250	rs301810	hCV3087000	rs1463055	0.51	0.515143538	0.7843
  hCV2987250	rs301810	hCV3087003	rs6577500	0.51	0.515143538	0.7843
  hCV2987250	rs301810	hCV3087015	rs11121198	0.51	0.515143538	0.8909
  hCV2987250	rs301810	hCV3087016	rs2297867	0.51	0.515143538	0.7731
  hCV2987250	rs301810	hCV32055284	rs12079653	0.51	0.515143538	0.6533
  hCV2987250	rs301810	hCV32055470	rs6577506	0.51	0.515143538	0.7754
  hCV2987250	rs301810	hCV32055474	rs10864359	0.51	0.515143538	0.665
  hCV2987250	rs301810	hCV32055477	rs10779705	0.51	0.515143538	0.6812
  hCV2987250	rs301810	hCV32055548	rs11121197	0.51	0.515143538	0.7843
  hCV2987250	rs301810	hCV32055579	rs6577522	0.51	0.515143538	0.6308
  hCV2987250	rs301810	hCV32055595	rs6577524	0.51	0.515143538	0.6312
  hCV2987250	rs301810	hCV32055637	rs6577532	0.51	0.515143538	0.5618
  hCV2987250	rs301810	hCV32055677	rs10864355	0.51	0.515143538	0.7843
  hCV2987250	rs301810	hCV529178	rs301811	0.51	0.515143538	0.8909
  hCV2987250	rs301810	hCV529182	rs301800	0.51	0.515143538	0.5618
  hCV2987250	rs301810	hCV597227	rs301809	0.51	0.515143538	0.8909
  hCV2987250	rs301810	hCV597229	rs301785	0.51	0.515143538	0.8909
  hCV2987250	rs301810	hCV877241	rs301788	0.51	0.515143538	0.6134
  hCV2987250	rs301810	hCV8823713	rs1472228	0.51	0.515143538	0.6126
  hCV2987250	rs301810	hCV8824288	rs910582	0.51	0.515143538	0.7843
  hCV2987250	rs301810	hCV8824394	rs1443929	0.51	0.515143538	0.5153
  hCV2987250	rs301810	hCV8824424	rs1058790	0.51	0.515143538	0.5823
  hCV2987250	rs301810	hCV8824425	rs1058791	0.51	0.515143538	0.5599
  hCV2987250	rs301810	hCV8881145	rs1038008	0.51	0.515143538	0.6812
  hCV2987250	rs301810	hCV8881146	rs1463054	0.51	0.515143538	0.7592
  hCV2987250	rs301810	hCV8881157	rs1535158	0.51	0.515143538	0.6812
  hCV2987250	rs301810	hCV8881161	rs926951	0.51	0.515143538	0.8853
  hCV29873524	rs7533113	hCV1188731	rs4908514	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV1188735	rs10864366	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV27157507	rs6664000	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV27157524	rs6577531	0.51	0.906005924	0.9353
  hCV29873524	rs7533113	hCV27884601	rs4908776	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV28023091	rs4908773	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV29368919	rs4908513	0.51	0.906005924	1
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  hCV29873524	rs7533113	hCV30035535	rs7518204	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV32055527	rs10864364	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV32055579	rs6577522	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV32055595	rs6577524	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV32055596	rs6577525	0.51	0.906005924	1
  hCV29873524	rs7533113	hCV32055637	rs6577532	0.51	0.906005924	0.9314
  hCV29873524	rs7533113	hCV8823713	rs1472228	0.51	0.906005924	1
  hCV2992252	rs6037651	hCV27992218	rs4813636	0.51	0.9	0.9257
  hCV2992252	rs6037651	hCV2992258	rs1018493	0.51	0.9	0.9613
  hCV29945430	rs7517436	hCV11398434	rs1812457	0.51	0.516826964	0.7979
  hCV29945430	rs7517436	hCV11398437	rs1817367	0.51	0.516826964	0.6548
  hCV29945430	rs7517436	hCV11675962	rs10746481	0.51	0.516826964	0.8704
  hCV29945430	rs7517436	hCV1188659	rs3820037	0.51	0.516826964	0.5447
  hCV29945430	rs7517436	hCV1188660	rs6660137	0.51	0.516826964	0.5538
  hCV29945430	rs7517436	hCV1188664	rs2765511	0.51	0.516826964	0.6126
  hCV29945430	rs7517436	hCV1188665	rs2781060	0.51	0.516826964	0.6354
  hCV29945430	rs7517436	hCV1188676	rs11121247	0.51	0.516826964	0.5538
  hCV29945430	rs7517436	hCV1188731	rs4908514	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV1188735	rs10864366	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV12040675	rs2038904	0.51	0.516826964	0.6126
  hCV29945430	rs7517436	hCV15882429	rs2289732	0.51	0.516826964	0.6247
  hCV29945430	rs7517436	hCV15932991	rs2781067	0.51	0.516826964	0.6188
  hCV29945430	rs7517436	hCV15932992	rs2781068	0.51	0.516826964	0.6121
  hCV29945430	rs7517436	hCV27157507	rs6664000	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV27157524	rs6577531	0.51	0.516826964	0.9314
  hCV29945430	rs7517436	hCV2741759	rs11121179	0.51	0.516826964	0.6713
  hCV29945430	rs7517436	hCV27474399	rs3753275	0.51	0.516826964	0.5807
  hCV29945430	rs7517436	hCV27884601	rs4908776	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV27958354	rs4908762	0.51	0.516826964	0.6717
  hCV29945430	rs7517436	hCV28023091	rs4908773	0.51	0.516826964	1
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  hCV29945430	rs7517436	hCV2943853	rs301793	0.51	0.516826964	0.6247
  hCV29945430	rs7517436	hCV2966436	rs11121174	0.51	0.516826964	0.6247
  hCV29945430	rs7517436	hCV2966437	rs11580417	0.51	0.516826964	0.6247
  hCV29945430	rs7517436	hCV2966441	rs6684863	0.51	0.516826964	0.6247
  hCV29945430	rs7517436	hCV2966444	rs11121171	0.51	0.516826964	0.6727
  hCV29945430	rs7517436	hCV29819064	rs6698079	0.51	0.516826964	0.7458
  hCV29945430	rs7517436	hCV2987250	rs301810	0.51	0.516826964	0.6126
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  hCV29945430	rs7517436	hCV29873526	rs6697997	0.51	0.516826964	0.6952
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  hCV29945430	rs7517436	hCV3086950	rs4908771	0.51	0.516826964	0.8704
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  hCV29945430	rs7517436	hCV3086972	rs6688329	0.51	0.516826964	0.8568
  hCV29945430	rs7517436	hCV3086998	rs7530863	0.51	0.516826964	0.6717
  hCV29945430	rs7517436	hCV3087000	rs1463055	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV3087003	rs6577500	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV3087015	rs11121198	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV3087016	rs2297867	0.51	0.516826964	0.6499
  hCV29945430	rs7517436	hCV32055284	rs12079653	0.51	0.516826964	0.6676
  hCV29945430	rs7517436	hCV32055470	rs6577506	0.51	0.516826964	0.7188
  hCV29945430	rs7517436	hCV32055474	rs10864359	0.51	0.516826964	0.6717
  hCV29945430	rs7517436	hCV32055477	rs10779705	0.51	0.516826964	0.7979
  hCV29945430	rs7517436	hCV32055527	rs10864364	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV32055548	rs11121197	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV32055579	rs6577522	0.51	0.516826964	1
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  hCV29945430	rs7517436	hCV32055596	rs6577525	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV32055625	rs6678590	0.51	0.516826964	0.8645
  hCV29945430	rs7517436	hCV32055637	rs6577532	0.51	0.516826964	0.8301
  hCV29945430	rs7517436	hCV32055662	rs6677249	0.51	0.516826964	0.645
  hCV29945430	rs7517436	hCV32055677	rs10864355	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV529178	rs301811	0.51	0.516826964	0.6949
  hCV29945430	rs7517436	hCV529182	rs301800	0.51	0.516826964	0.6998
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  hCV29945430	rs7517436	hCV597229	rs301785	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV877241	rs301788	0.51	0.516826964	0.6713
  hCV29945430	rs7517436	hCV8823713	rs1472228	0.51	0.516826964	1
  hCV29945430	rs7517436	hCV8824244	rs1006950	0.51	0.516826964	0.574
  hCV29945430	rs7517436	hCV8824248	rs1543711	0.51	0.516826964	0.6126
  hCV29945430	rs7517436	hCV8824288	rs910582	0.51	0.516826964	0.6952
  hCV29945430	rs7517436	hCV8824394	rs1443929	0.51	0.516826964	0.6713
  hCV29945430	rs7517436	hCV8824424	rs1058790	0.51	0.516826964	0.6727
  hCV29945430	rs7517436	hCV8824425	rs1058791	0.51	0.516826964	0.6383
  hCV29945430	rs7517436	hCV8881145	rs1038008	0.51	0.516826964	0.7979
  hCV29945430	rs7517436	hCV8881146	rs1463054	0.51	0.516826964	0.8032
  hCV29945430	rs7517436	hCV8881157	rs1535158	0.51	0.516826964	0.7979
  hCV29945430	rs7517436	hCV8881161	rs926951	0.51	0.516826964	0.6717
  hCV29952522	rs9457931	hCV16072675	rs2130087	0.51	0.408966509	0.7435
  hCV29952522	rs9457931	hCV27502709	rs3798158	0.51	0.408966509	0.7431
  hCV29952522	rs9457931	hCV29109993	rs7757997	0.51	0.408966509	1
  hCV29952522	rs9457931	hCV29109993	rs7757997	0.51	0.838470755	1
  hCV29952522	rs9457931	hCV29683578	rs7761031	0.51	0.408966509	1
  hCV29952522	rs9457931	hCV29683578	rs7761031	0.51	0.838470755	1
  hCV29952522	rs9457931	hCV29774032	rs9457881	0.51	0.408966509	1
  hCV29952522	rs9457931	hCV29774032	rs9457881	0.51	0.838470755	1
  hCV29952522	rs9457931	hCV29809835	rs9457880	0.51	0.408966509	0.7436
  hCV29952522	rs9457931	hCV30296556	rs10499313	0.51	0.408966509	0.7436
  hCV29952522	rs9457931	hCV30350563	rs9457882	0.51	0.408966509	0.7436
  hCV30136303	rs6914527	hCV11542275	rs3105258	0.51	0.9	0.9295
  hCV30136303	rs6914527	hCV11542286	rs3125275	0.51	0.9	1
  hCV30136303	rs6914527	hCV11559368	rs6899649	0.51	0.9	0.9428
  hCV30136303	rs6914527	hCV11560148	rs11966562	0.51	0.9	0.9048
  hCV30136303	rs6914527	hCV12026670	rs2047809	0.51	0.9	0.9244
  hCV30136303	rs6914527	hCV238179	rs9370364	0.51	0.9	1
  hCV30136303	rs6914527	hCV238181	rs11968305	0.51	0.9	0.9244
  hCV30136303	rs6914527	hCV238185	rs6914267	0.51	0.9	1
  hCV30136303	rs6914527	hCV26549031	rs6907460	0.51	0.9	0.9616
  hCV30136303	rs6914527	hCV26549047	rs4518493	0.51	0.9	0.9226
  hCV30136303	rs6914527	hCV26549113	rs4236122	0.51	0.9	0.9161
  hCV30136303	rs6914527	hCV27953375	rs4712088	0.51	0.9	0.9048
  hCV30136303	rs6914527	hCV27975017	rs4398735	0.51	0.9	0.9244
  hCV30136303	rs6914527	hCV29161721	rs6915903	0.51	0.9	0.9309
  hCV30136303	rs6914527	hCV29161723	rs7766969	0.51	0.9	0.9244
  hCV30136303	rs6914527	hCV30225897	rs9357829	0.51	0.9	0.9309
  hCV30136303	rs6914527	hCV358624	rs4715508	0.51	0.9	0.9036
  hCV30136303	rs6914527	hCV461035	rs7746448	0.51	0.9	0.9415
  hCV30233466	rs7513880	hCV1188706	rs2185205	0.51	0.771664644	0.8883
  hCV30233466	rs7513880	hCV1188726	rs6698830	0.51	0.771664644	1
  hCV30233466	rs7513880	hCV1188747	rs4908511	0.51	0.771664644	0.8871
  hCV30233466	rs7513880	hCV1188748	rs12028160	0.51	0.771664644	0.9066
  hCV30233466	rs7513880	hCV29855298	rs6690928	0.51	0.771664644	1
  hCV30233466	rs7513880	hCV29981708	rs7554486	0.51	0.771664644	0.7756
  hCV30233466	rs7513880	hCV32055554	rs12024032	0.51	0.771664644	0.9066
  hCV30233466	rs7513880	hCV32055587	rs10864367	0.51	0.771664644	1
  hCV30233466	rs7513880	hCV32055630	rs4908518	0.51	0.771664644	0.8883
  hCV30233466	rs7513880	hDV75072264	rs12403640	0.51	0.771664644	0.8888
  hCV3026189	rs11739136	hCV15861099	rs2071161	0.51	0.9	1
  hCV30264691	rs10508518	hCV29218874	rs7087976	0.51	0.9	1
  hCV30264691	rs10508518	hCV29218875	rs7087834	0.51	0.9	1
  hCV30264691	rs10508518	hCV3134992	rs4748342	0.51	0.9	1
  hCV30264691	rs10508518	hCV3135019	rs7897550	0.51	0.9	0.9123
  hCV30264691	rs10508518	hDV72006105	rs7916443	0.51	0.9	1
  hCV30287627	rs6675443	hCV11398047	rs1922983	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV11398445	rs1934138	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV11675339	rs7530745	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV11675982	rs1953827	0.51	0.758102092	0.9521
  hCV30287627	rs6675443	hCV11675985	rs12136766	0.51	0.758102092	0.9521
  hCV30287627	rs6675443	hCV1265820	rs6577488	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV1265823	rs1024197	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV1265830	rs7551849	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV1265841	rs10864354	0.51	0.758102092	0.8743
  hCV30287627	rs6675443	hCV1265857	rs10864356	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV1265858	rs11121194	0.51	0.758102092	0.9511
  hCV30287627	rs6675443	hCV1265860	rs6577491	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV1265866	rs6577496	0.51	0.758102092	0.9069
  hCV30287627	rs6675443	hCV16007535	rs2401138	0.51	0.758102092	0.9093
  hCV30287627	rs6675443	hCV27157433	rs7544052	0.51	0.758102092	0.866
  hCV30287627	rs6675443	hCV27157435	rs7513420	0.51	0.758102092	0.8672
  hCV30287627	rs6675443	hCV27157439	rs10779704	0.51	0.758102092	0.894
  hCV30287627	rs6675443	hCV27157529	rs1463049	0.51	0.758102092	0.9062
  hCV30287627	rs6675443	hCV27157851	rs4480384	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV27979869	rs4908760	0.51	0.758102092	0.8685
  hCV30287627	rs6675443	hCV29368911	rs6577513	0.51	0.758102092	0.9041
  hCV30287627	rs6675443	hCV29368927	rs6577499	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV29368929	rs6577502	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV29674579	rs7542312	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV30341660	rs6681362	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV30413939	rs6701331	0.51	0.758102092	0.9521
  hCV30287627	rs6675443	hCV30413946	rs7537982	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086941	rs7556169	0.51	0.758102092	0.9047
  hCV30287627	rs6675443	hCV3086945	rs6695867	0.51	0.758102092	0.9531
  hCV30287627	rs6675443	hCV3086948	rs10864361	0.51	0.758102092	0.8606
  hCV30287627	rs6675443	hCV3086949	rs11121212	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV3086952	rs6577514	0.51	0.758102092	0.9061
  hCV30287627	rs6675443	hCV3086954	rs1463053	0.51	0.758102092	0.9047
  hCV30287627	rs6675443	hCV3086956	rs1463052	0.51	0.758102092	0.9521
  hCV30287627	rs6675443	hCV3086959	rs7520025	0.51	0.758102092	0.9547
  hCV30287627	rs6675443	hCV3086965	rs1381928	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086974	rs1318218	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086976	rs11121204	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086978	rs7526171	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086981	rs6670508	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086985	rs6663123	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3086990	rs11121202	0.51	0.758102092	1
  hCV30287627	rs6675443	hCV3087002	rs1473420	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV3087004	rs2016084	0.51	0.758102092	0.8312
  hCV30287627	rs6675443	hCV3087005	rs6702060	0.51	0.758102092	0.9129
  hCV30287627	rs6675443	hCV3087012	rs1463051	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV32055336	rs12080583	0.51	0.758102092	0.9111
  hCV30287627	rs6675443	hCV32055351	rs12046643	0.51	0.758102092	0.9111
  hCV30287627	rs6675443	hCV32055354	rs4908761	0.51	0.758102092	0.9069
  hCV30287627	rs6675443	hCV32055465	rs6668508	0.51	0.758102092	0.9094
  hCV30287627	rs6675443	hCV32055479	rs11121210	0.51	0.758102092	0.9543
  hCV30287627	rs6675443	hCV32055489	rs10864360	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV32055490	rs6669503	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV32055496	rs11121215	0.51	0.758102092	0.9093
  hCV30287627	rs6675443	hCV32055498	rs4908507	0.51	0.758102092	0.9531
  hCV30287627	rs6675443	hCV32055588	rs12131864	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV32056071	rs11121201	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV32392515	rs4908505	0.51	0.758102092	0.8606
  hCV30287627	rs6675443	hCV597221	rs301814	0.51	0.758102092	0.9135
  hCV30287627	rs6675443	hCV8881153	rs1061039	0.51	0.758102092	1
  hCV30287627	rs6675443	hDV77058075	rs4908506	0.51	0.758102092	0.9047
  hCV30454150	rs10516434	hCV28960525	rs6532740	0.51	0.9	0.9227
  hCV30454150	rs10516434	hCV28960526	rs6853079	0.51	0.9	0.9309
  hCV30454150	rs10516434	hCV29480044	rs10516433	0.51	0.9	0.9309
  hCV30454150	rs10516434	hCV30694936	rs6840610	0.51	0.9	0.9309
  hCV30454150	rs10516434	hDV70961198	rs17498778	0.51	0.9	0.9309
  hCV30454150	rs10516434	hDV70969482	rs17564872	0.51	0.9	0.9309
  hCV30454150	rs10516434	hDV71951446	rs7689289	0.51	0.9	0.9309
  hCV30467730	rs6702457	hCV11398434	rs1812457	0.51	0.534550731	0.9381
  hCV30467730	rs6702457	hCV11398437	rs1817367	0.51	0.534550731	0.9276
  hCV30467730	rs6702457	hCV11675962	rs10746481	0.51	0.534550731	1
  hCV30467730	rs6702457	hCV1188664	rs2765511	0.51	0.534550731	0.54
  hCV30467730	rs6702457	hCV1188665	rs2781060	0.51	0.534550731	0.556
  hCV30467730	rs6702457	hCV1188731	rs4908514	0.51	0.534550731	0.8774
  hCV30467730	rs6702457	hCV1188735	rs10864366	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV12040675	rs2038904	0.51	0.534550731	0.54
  hCV30467730	rs6702457	hCV15882429	rs2289732	0.51	0.534550731	0.5549
  hCV30467730	rs6702457	hCV15932991	rs2781067	0.51	0.534550731	0.5861
  hCV30467730	rs6702457	hCV15932992	rs2781068	0.51	0.534550731	0.5389
  hCV30467730	rs6702457	hCV27157507	rs6664000	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV27157524	rs6577531	0.51	0.534550731	0.8175
  hCV30467730	rs6702457	hCV27884601	rs4908776	0.51	0.534550731	0.877
  hCV30467730	rs6702457	hCV27958354	rs4908762	0.51	0.534550731	0.815
  hCV30467730	rs6702457	hCV28023091	rs4908773	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV29368919	rs4908513	0.51	0.534550731	0.8774
  hCV30467730	rs6702457	hCV2943451	rs902355	0.51	0.534550731	0.6259
  hCV30467730	rs6702457	hCV2943853	rs301793	0.51	0.534550731	0.5549
  hCV30467730	rs6702457	hCV2966436	rs11121174	0.51	0.534550731	0.5549
  hCV30467730	rs6702457	hCV2966437	rs11580417	0.51	0.534550731	0.5549
  hCV30467730	rs6702457	hCV2966441	rs6684863	0.51	0.534550731	0.5549
  hCV30467730	rs6702457	hCV2966444	rs11121171	0.51	0.534550731	0.5975
  hCV30467730	rs6702457	hCV29819064	rs6698079	0.51	0.534550731	0.919
  hCV30467730	rs6702457	hCV2987250	rs301810	0.51	0.534550731	0.633
  hCV30467730	rs6702457	hCV29873524	rs7533113	0.51	0.534550731	0.8774
  hCV30467730	rs6702457	hCV29873526	rs6697997	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV29945430	rs7517436	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV30035535	rs7518204	0.51	0.534550731	0.877
  hCV30467730	rs6702457	hCV30125699	rs4581300	0.51	0.534550731	0.815
  hCV30467730	rs6702457	hCV30143725	rs6690050	0.51	0.534550731	0.8785
  hCV30467730	rs6702457	hCV3086930	rs6658881	0.51	0.534550731	1
  hCV30467730	rs6702457	hCV3086932	rs7533442	0.51	0.534550731	1
  hCV30467730	rs6702457	hCV3086950	rs4908771	0.51	0.534550731	1
  hCV30467730	rs6702457	hCV3086961	rs6703577	0.51	0.534550731	0.9345
  hCV30467730	rs6702457	hCV3086971	rs6679948	0.51	0.534550731	0.9381
  hCV30467730	rs6702457	hCV3086972	rs6688329	0.51	0.534550731	0.9345
  hCV30467730	rs6702457	hCV3086998	rs7530863	0.51	0.534550731	0.815
  hCV30467730	rs6702457	hCV3087000	rs1463055	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV3087003	rs6577500	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV3087015	rs11121198	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV3087016	rs2297867	0.51	0.534550731	0.815
  hCV30467730	rs6702457	hCV32055284	rs12079653	0.51	0.534550731	0.6352
  hCV30467730	rs6702457	hCV32055470	rs6577506	0.51	0.534550731	0.9345
  hCV30467730	rs6702457	hCV32055474	rs10864359	0.51	0.534550731	0.9345
  hCV30467730	rs6702457	hCV32055477	rs10779705	0.51	0.534550731	0.9381
  hCV30467730	rs6702457	hCV32055527	rs10864364	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV32055548	rs11121197	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV32055579	rs6577522	0.51	0.534550731	0.8774
  hCV30467730	rs6702457	hCV32055595	rs6577524	0.51	0.534550731	0.8774
  hCV30467730	rs6702457	hCV32055596	rs6577525	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV32055625	rs6678590	0.51	0.534550731	0.7684
  hCV30467730	rs6702457	hCV32055637	rs6577532	0.51	0.534550731	0.8069
  hCV30467730	rs6702457	hCV32055662	rs6677249	0.51	0.534550731	0.6372
  hCV30467730	rs6702457	hCV32055677	rs10864355	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV529178	rs301811	0.51	0.534550731	0.8246
  hCV30467730	rs6702457	hCV529182	rs301800	0.51	0.534550731	0.5758
  hCV30467730	rs6702457	hCV597227	rs301809	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV597229	rs301785	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV8823713	rs1472228	0.51	0.534550731	0.8704
  hCV30467730	rs6702457	hCV8824248	rs1543711	0.51	0.534550731	0.54
  hCV30467730	rs6702457	hCV8824288	rs910582	0.51	0.534550731	0.8248
  hCV30467730	rs6702457	hCV8824424	rs1058790	0.51	0.534550731	0.5975
  hCV30467730	rs6702457	hCV8824425	rs1058791	0.51	0.534550731	0.5737
  hCV30467730	rs6702457	hCV8881145	rs1038008	0.51	0.534550731	0.9381
  hCV30467730	rs6702457	hCV8881146	rs1463054	0.51	0.534550731	0.9064
  hCV30467730	rs6702457	hCV8881157	rs1535158	0.51	0.534550731	0.9381
  hCV30467730	rs6702457	hCV8881161	rs926951	0.51	0.534550731	0.815
  hCV30534667	rs4996259	hCV26718978	rs7779312	0.51	0.9	0.9383
  hCV30534667	rs4996259	hCV2677705	rs12670134	0.51	0.9	0.9021
  hCV30534667	rs4996259	hCV2677722	rs1548868	0.51	0.9	1
  hCV30534667	rs4996259	hCV2677723	rs3735442	0.51	0.9	1
  hCV30534667	rs4996259	hCV29210278	rs7784056	0.51	0.9	1
  hCV30586985	rs10126006	hCV11373123	rs1984003	0.51	0.485664418	0.6184
  hCV30586985	rs10126006	hCV11765727	rs10781379	0.51	0.485664418	0.6121
  hCV30586985	rs10126006	hCV11765729	rs7875659	0.51	0.485664418	0.6108
  hCV30586985	rs10126006	hCV11765753	rs3793456	0.51	0.485664418	0.8904
  hCV30586985	rs10126006	hCV1463101	rs7871596	0.51	0.485664418	0.6831
  hCV30586985	rs10126006	hCV1463112	rs3763608	0.51	0.485664418	0.8497
  hCV30586985	rs10126006	hCV1463185	rs953588	0.51	0.485664418	0.5648
  hCV30586985	rs10126006	hCV1463216	rs4745581	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV1463218	rs1984004	0.51	0.485664418	0.6
  hCV30586985	rs10126006	hCV1463222	rs4744808	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV1463225	rs4745577	0.51	0.485664418	0.6184
  hCV30586985	rs10126006	hCV1463226	rs10890	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV1463232	rs9314854	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV1463235	rs2498430	0.51	0.485664418	0.6815
  hCV30586985	rs10126006	hCV1463244	rs3793465	0.51	0.485664418	0.9422
  hCV30586985	rs10126006	hCV1463247	rs3829064	0.51	0.485664418	0.6431
  hCV30586985	rs10126006	hCV1463251	rs2498434	0.51	0.485664418	0.7097
  hCV30586985	rs10126006	hCV1463252	rs3793461	0.51	0.485664418	0.9284
  hCV30586985	rs10126006	hCV1463256	rs2309394	0.51	0.485664418	0.7296
  hCV30586985	rs10126006	hCV15761059	rs2309393	0.51	0.485664418	0.9422
  hCV30586985	rs10126006	hCV15892414	rs2498431	0.51	0.485664418	0.6815
  hCV30586985	rs10126006	hCV15892430	rs2498433	0.51	0.485664418	0.5477
  hCV30586985	rs10126006	hCV25609765	rs3829062	0.51	0.485664418	0.7296
  hCV30586985	rs10126006	hCV26566199	rs3793467	0.51	0.485664418	0.9284
  hCV30586985	rs10126006	hCV26566299	rs10869821	0.51	0.485664418	0.6497
  hCV30586985	rs10126006	hCV27517372	rs3793457	0.51	0.485664418	0.67
  hCV30586985	rs10126006	hCV28008078	rs4745543	0.51	0.485664418	0.8573
  hCV30586985	rs10126006	hCV29861776	rs9411171	0.51	0.485664418	0.6431
  hCV30586985	rs10126006	hCV31363797	rs11145043	0.51	0.485664418	0.9036
  hCV30586985	rs10126006	hCV31363840	rs7875693	0.51	0.485664418	0.8834
  hCV30586985	rs10126006	hCV31363841	rs7849347	0.51	0.485664418	0.8548
  hCV30586985	rs10126006	hCV31363869	rs11145070	0.51	0.485664418	0.6279
  hCV30586985	rs10126006	hCV31363888	rs7859021	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV31363984	rs7855905	0.51	0.485664418	0.8671
  hCV30586985	rs10126006	hCV320569	rs9411170	0.51	0.485664418	0.6762
  hCV30586985	rs10126006	hCV8785184	rs1411676	0.51	0.485664418	0.6184
  hCV30586985	rs10126006	hCV8785185	rs1411675	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hCV9333267	rs1045632	0.51	0.485664418	0.6289
  hCV30586985	rs10126006	hDV71871695	rs7047274	0.51	0.485664418	0.6902
  hCV30606396	rs10438978	hCV15846640	rs2187375	0.51	0.9	0.9391
  hCV30606396	rs10438978	hCV16140621	rs2156552	0.51	0.9	0.9392
  hCV30606396	rs10438978	hCV27889421	rs4939883	0.51	0.9	1
  hCV30606396	rs10438978	hCV29202191	rs7240405	0.51	0.9	0.9694
  hCV30606396	rs10438978	hCV29202193	rs7239867	0.51	0.9	0.9694
  hCV30606396	rs10438978	hCV29202195	rs8086351	0.51	0.9	0.9438
  hCV30606396	rs10438978	hCV30011938	rs7241918	0.51	0.9	1
  hCV30606396	rs10438978	hDV71197604	rs1943981	0.51	0.9	0.9459
  hCV30764105	rs12521915	hCV15758655	rs2303122	0.51	0.9	1
  hCV30764105	rs12521915	hCV2929716	rs7725246	0.51	0.9	0.9371
  hCV3086932	rs7533442	hCV11398434	rs1812457	0.51	0.411159327	0.9345
  hCV3086932	rs7533442	hCV11398437	rs1817367	0.51	0.411159327	0.8687
  hCV3086932	rs7533442	hCV11675962	rs10746481	0.51	0.411159327	1
  hCV3086932	rs7533442	hCV1188659	rs3820037	0.51	0.411159327	0.4725
  hCV3086932	rs7533442	hCV1188660	rs6660137	0.51	0.411159327	0.4816
  hCV3086932	rs7533442	hCV1188664	rs2765511	0.51	0.411159327	0.5167
  hCV3086932	rs7533442	hCV1188665	rs2781060	0.51	0.411159327	0.5328
  hCV3086932	rs7533442	hCV1188676	rs11121247	0.51	0.411159327	0.4816
  hCV3086932	rs7533442	hCV1188731	rs4908514	0.51	0.411159327	0.8704
  hCV3086932	rs7533442	hCV1188735	rs10864366	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV12040675	rs2038904	0.51	0.411159327	0.5167
  hCV3086932	rs7533442	hCV15882429	rs2289732	0.51	0.411159327	0.5302
  hCV3086932	rs7533442	hCV15932991	rs2781067	0.51	0.411159327	0.5621
  hCV3086932	rs7533442	hCV15932992	rs2781068	0.51	0.411159327	0.5153
  hCV3086932	rs7533442	hCV27157507	rs6664000	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV27157524	rs6577531	0.51	0.411159327	0.8069
  hCV3086932	rs7533442	hCV2741759	rs11121179	0.51	0.411159327	0.5418
  hCV3086932	rs7533442	hCV27474399	rs3753275	0.51	0.411159327	0.4658
  hCV3086932	rs7533442	hCV27884601	rs4908776	0.51	0.411159327	0.87
  hCV3086932	rs7533442	hCV27958354	rs4908762	0.51	0.411159327	0.8501
  hCV3086932	rs7533442	hCV28023091	rs4908773	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV29368919	rs4908513	0.51	0.411159327	0.8704
  hCV3086932	rs7533442	hCV2943451	rs902355	0.51	0.411159327	0.6039
  hCV3086932	rs7533442	hCV2943853	rs301793	0.51	0.411159327	0.5302
  hCV3086932	rs7533442	hCV2966436	rs11121174	0.51	0.411159327	0.5302
  hCV3086932	rs7533442	hCV2966437	rs11580417	0.51	0.411159327	0.5302
  hCV3086932	rs7533442	hCV2966441	rs6684863	0.51	0.411159327	0.5302
  hCV3086932	rs7533442	hCV2966444	rs11121171	0.51	0.411159327	0.5747
  hCV3086932	rs7533442	hCV29819064	rs6698079	0.51	0.411159327	0.9184
  hCV3086932	rs7533442	hCV2987250	rs301810	0.51	0.411159327	0.7185
  hCV3086932	rs7533442	hCV29873524	rs7533113	0.51	0.411159327	0.8704
  hCV3086932	rs7533442	hCV29873526	rs6697997	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV29945430	rs7517436	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV30035535	rs7518204	0.51	0.411159327	0.87
  hCV3086932	rs7533442	hCV30125699	rs4581300	0.51	0.411159327	0.7911
  hCV3086932	rs7533442	hCV30143725	rs6690050	0.51	0.411159327	0.8714
  hCV3086932	rs7533442	hCV30287627	rs6675443	0.51	0.411159327	0.4429
  hCV3086932	rs7533442	hCV30341660	rs6681362	0.51	0.411159327	0.4193
  hCV3086932	rs7533442	hCV30467730	rs6702457	0.51	0.411159327	1
  hCV3086932	rs7533442	hCV3086930	rs6658881	0.51	0.411159327	1
  hCV3086932	rs7533442	hCV3086941	rs7556169	0.51	0.411159327	0.4162
  hCV3086932	rs7533442	hCV3086950	rs4908771	0.51	0.411159327	1
  hCV3086932	rs7533442	hCV3086952	rs6577514	0.51	0.411159327	0.464
  hCV3086932	rs7533442	hCV3086961	rs6703577	0.51	0.411159327	0.9091
  hCV3086932	rs7533442	hCV3086971	rs6679948	0.51	0.411159327	0.9345
  hCV3086932	rs7533442	hCV3086972	rs6688329	0.51	0.411159327	0.9305
  hCV3086932	rs7533442	hCV3086978	rs7526171	0.51	0.411159327	0.439
  hCV3086932	rs7533442	hCV3086998	rs7530863	0.51	0.411159327	0.8501
  hCV3086932	rs7533442	hCV3087000	rs1463055	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV3087003	rs6577500	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV3087015	rs11121198	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV3087016	rs2297867	0.51	0.411159327	0.8228
  hCV3086932	rs7533442	hCV32055284	rs12079653	0.51	0.411159327	0.6146
  hCV3086932	rs7533442	hCV32055470	rs6577506	0.51	0.411159327	0.9091
  hCV3086932	rs7533442	hCV32055474	rs10864359	0.51	0.411159327	0.85
  hCV3086932	rs7533442	hCV32055477	rs10779705	0.51	0.411159327	0.9345
  hCV3086932	rs7533442	hCV32055496	rs11121215	0.51	0.411159327	0.4393
  hCV3086932	rs7533442	hCV32055527	rs10864364	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV32055548	rs11121197	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV32055579	rs6577522	0.51	0.411159327	0.8704
  hCV3086932	rs7533442	hCV32055595	rs6577524	0.51	0.411159327	0.8704
  hCV3086932	rs7533442	hCV32055596	rs6577525	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV32055625	rs6678590	0.51	0.411159327	0.7419
  hCV3086932	rs7533442	hCV32055637	rs6577532	0.51	0.411159327	0.6768
  hCV3086932	rs7533442	hCV32055662	rs6677249	0.51	0.411159327	0.5186
  hCV3086932	rs7533442	hCV32055677	rs10864355	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV529178	rs301811	0.51	0.411159327	0.8149
  hCV3086932	rs7533442	hCV529182	rs301800	0.51	0.411159327	0.5676
  hCV3086932	rs7533442	hCV597227	rs301809	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV597229	rs301785	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV877241	rs301788	0.51	0.411159327	0.5418
  hCV3086932	rs7533442	hCV8823713	rs1472228	0.51	0.411159327	0.8213
  hCV3086932	rs7533442	hCV8824244	rs1006950	0.51	0.411159327	0.4725
  hCV3086932	rs7533442	hCV8824248	rs1543711	0.51	0.411159327	0.5167
  hCV3086932	rs7533442	hCV8824288	rs910582	0.51	0.411159327	0.815
  hCV3086932	rs7533442	hCV8824394	rs1443929	0.51	0.411159327	0.5418
  hCV3086932	rs7533442	hCV8824424	rs1058790	0.51	0.411159327	0.5747
  hCV3086932	rs7533442	hCV8824425	rs1058791	0.51	0.411159327	0.5144
  hCV3086932	rs7533442	hCV8881145	rs1038008	0.51	0.411159327	0.9345
  hCV3086932	rs7533442	hCV8881146	rs1463054	0.51	0.411159327	0.9059
  hCV3086932	rs7533442	hCV8881157	rs1535158	0.51	0.411159327	0.9345
  hCV3086932	rs7533442	hCV8881161	rs926951	0.51	0.411159327	0.8501
  hCV3086932	rs7533442	hDV77058075	rs4908506	0.51	0.411159327	0.4162
  hCV3086950	rs4908771	hCV11398434	rs1812457	0.51	0.532308891	0.9381
  hCV3086950	rs4908771	hCV11398437	rs1817367	0.51	0.532308891	0.9276
  hCV3086950	rs4908771	hCV11675962	rs10746481	0.51	0.532308891	1
  hCV3086950	rs4908771	hCV1188664	rs2765511	0.51	0.532308891	0.54
  hCV3086950	rs4908771	hCV1188665	rs2781060	0.51	0.532308891	0.556
  hCV3086950	rs4908771	hCV1188731	rs4908514	0.51	0.532308891	0.8774
  hCV3086950	rs4908771	hCV1188735	rs10864366	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV12040675	rs2038904	0.51	0.532308891	0.54
  hCV3086950	rs4908771	hCV15882429	rs2289732	0.51	0.532308891	0.5549
  hCV3086950	rs4908771	hCV15932991	rs2781067	0.51	0.532308891	0.5861
  hCV3086950	rs4908771	hCV15932992	rs2781068	0.51	0.532308891	0.5389
  hCV3086950	rs4908771	hCV27157507	rs6664000	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV27157524	rs6577531	0.51	0.532308891	0.8175
  hCV3086950	rs4908771	hCV27884601	rs4908776	0.51	0.532308891	0.877
  hCV3086950	rs4908771	hCV27958354	rs4908762	0.51	0.532308891	0.815
  hCV3086950	rs4908771	hCV28023091	rs4908773	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV29368919	rs4908513	0.51	0.532308891	0.8774
  hCV3086950	rs4908771	hCV2943451	rs902355	0.51	0.532308891	0.6259
  hCV3086950	rs4908771	hCV2943853	rs301793	0.51	0.532308891	0.5549
  hCV3086950	rs4908771	hCV2966436	rs11121174	0.51	0.532308891	0.5549
  hCV3086950	rs4908771	hCV2966437	rs11580417	0.51	0.532308891	0.5549
  hCV3086950	rs4908771	hCV2966441	rs6684863	0.51	0.532308891	0.5549
  hCV3086950	rs4908771	hCV2966444	rs11121171	0.51	0.532308891	0.5975
  hCV3086950	rs4908771	hCV29819064	rs6698079	0.51	0.532308891	0.919
  hCV3086950	rs4908771	hCV2987250	rs301810	0.51	0.532308891	0.7323
  hCV3086950	rs4908771	hCV29873524	rs7533113	0.51	0.532308891	0.8774
  hCV3086950	rs4908771	hCV29873526	rs6697997	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV29945430	rs7517436	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV30035535	rs7518204	0.51	0.532308891	0.877
  hCV3086950	rs4908771	hCV30125699	rs4581300	0.51	0.532308891	0.815
  hCV3086950	rs4908771	hCV30143725	rs6690050	0.51	0.532308891	0.8785
  hCV3086950	rs4908771	hCV30467730	rs6702457	0.51	0.532308891	1
  hCV3086950	rs4908771	hCV3086930	rs6658881	0.51	0.532308891	1
  hCV3086950	rs4908771	hCV3086932	rs7533442	0.51	0.532308891	1
  hCV3086950	rs4908771	hCV3086961	rs6703577	0.51	0.532308891	0.9345
  hCV3086950	rs4908771	hCV3086971	rs6679948	0.51	0.532308891	0.9381
  hCV3086950	rs4908771	hCV3086972	rs6688329	0.51	0.532308891	0.9345
  hCV3086950	rs4908771	hCV3086998	rs7530863	0.51	0.532308891	0.815
  hCV3086950	rs4908771	hCV3087000	rs1463055	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV3087003	rs6577500	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV3087015	rs11121198	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV3087016	rs2297867	0.51	0.532308891	0.815
  hCV3086950	rs4908771	hCV32055284	rs12079653	0.51	0.532308891	0.6352
  hCV3086950	rs4908771	hCV32055470	rs6577506	0.51	0.532308891	0.9345
  hCV3086950	rs4908771	hCV32055474	rs10864359	0.51	0.532308891	0.9345
  hCV3086950	rs4908771	hCV32055477	rs10779705	0.51	0.532308891	0.9381
  hCV3086950	rs4908771	hCV32055527	rs10864364	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV32055548	rs11121197	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV32055579	rs6577522	0.51	0.532308891	0.8774
  hCV3086950	rs4908771	hCV32055595	rs6577524	0.51	0.532308891	0.8774
  hCV3086950	rs4908771	hCV32055596	rs6577525	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV32055625	rs6678590	0.51	0.532308891	0.7684
  hCV3086950	rs4908771	hCV32055637	rs6577532	0.51	0.532308891	0.8069
  hCV3086950	rs4908771	hCV32055662	rs6677249	0.51	0.532308891	0.6372
  hCV3086950	rs4908771	hCV32055677	rs10864355	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV529178	rs301811	0.51	0.532308891	0.8246
  hCV3086950	rs4908771	hCV529182	rs301800	0.51	0.532308891	0.5758
  hCV3086950	rs4908771	hCV597227	rs301809	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV597229	rs301785	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV8823713	rs1472228	0.51	0.532308891	0.8704
  hCV3086950	rs4908771	hCV8824248	rs1543711	0.51	0.532308891	0.54
  hCV3086950	rs4908771	hCV8824288	rs910582	0.51	0.532308891	0.8248
  hCV3086950	rs4908771	hCV8824424	rs1058790	0.51	0.532308891	0.5975
  hCV3086950	rs4908771	hCV8824425	rs1058791	0.51	0.532308891	0.5737
  hCV3086950	rs4908771	hCV8881145	rs1038008	0.51	0.532308891	0.9381
  hCV3086950	rs4908771	hCV8881146	rs1463054	0.51	0.532308891	0.9064
  hCV3086950	rs4908771	hCV8881157	rs1535158	0.51	0.532308891	0.9381
  hCV3086950	rs4908771	hCV8881161	rs926951	0.51	0.532308891	0.815
  hCV3086961	rs6703577	hCV11398434	rs1812457	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV11398437	rs1817367	0.51	0.900934013	0.9642
  hCV3086961	rs6703577	hCV11675962	rs10746481	0.51	0.900934013	0.9345
  hCV3086961	rs6703577	hCV27958354	rs4908762	0.51	0.900934013	0.9379
  hCV3086961	rs6703577	hCV29819064	rs6698079	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV30143725	rs6690050	0.51	0.900934013	0.9345
  hCV3086961	rs6703577	hCV30467730	rs6702457	0.51	0.900934013	0.9345
  hCV3086961	rs6703577	hCV3086930	rs6658881	0.51	0.900934013	0.9091
  hCV3086961	rs6703577	hCV3086932	rs7533442	0.51	0.900934013	0.9091
  hCV3086961	rs6703577	hCV3086950	rs4908771	0.51	0.900934013	0.9345
  hCV3086961	rs6703577	hCV3086971	rs6679948	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV3086972	rs6688329	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV3086998	rs7530863	0.51	0.900934013	0.9379
  hCV3086961	rs6703577	hCV3087016	rs2297867	0.51	0.900934013	0.9091
  hCV3086961	rs6703577	hCV32055470	rs6577506	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV32055474	rs10864359	0.51	0.900934013	0.9379
  hCV3086961	rs6703577	hCV32055477	rs10779705	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV8881145	rs1038008	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV8881146	rs1463054	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV8881157	rs1535158	0.51	0.900934013	1
  hCV3086961	rs6703577	hCV8881161	rs926951	0.51	0.900934013	0.9379
  hCV3087000	rs1463055	hCV11398434	rs1812457	0.51	0.532906869	0.8824
  hCV3087000	rs1463055	hCV11398437	rs1817367	0.51	0.532906869	0.8638
  hCV3087000	rs1463055	hCV11675962	rs10746481	0.51	0.532906869	0.8248
  hCV3087000	rs1463055	hCV1188731	rs4908514	0.51	0.532906869	0.7112
  hCV3087000	rs1463055	hCV1188735	rs10864366	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV15882429	rs2289732	0.51	0.532906869	0.7153
  hCV3087000	rs1463055	hCV25996298	rs7535752	0.51	0.532906869	0.5809
  hCV3087000	rs1463055	hCV27157507	rs6664000	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV27157524	rs6577531	0.51	0.532906869	0.6596
  hCV3087000	rs1463055	hCV2741759	rs11121179	0.51	0.532906869	0.6996
  hCV3087000	rs1463055	hCV27474399	rs3753275	0.51	0.532906869	0.5827
  hCV3087000	rs1463055	hCV27884601	rs4908776	0.51	0.532906869	0.7103
  hCV3087000	rs1463055	hCV27958354	rs4908762	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV28023091	rs4908773	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV29368919	rs4908513	0.51	0.532906869	0.7112
  hCV3087000	rs1463055	hCV2943451	rs902355	0.51	0.532906869	0.7442
  hCV3087000	rs1463055	hCV2943853	rs301793	0.51	0.532906869	0.7153
  hCV3087000	rs1463055	hCV2966436	rs11121174	0.51	0.532906869	0.7153
  hCV3087000	rs1463055	hCV2966437	rs11580417	0.51	0.532906869	0.7153
  hCV3087000	rs1463055	hCV2966441	rs6684863	0.51	0.532906869	0.7153
  hCV3087000	rs1463055	hCV2966444	rs11121171	0.51	0.532906869	0.7672
  hCV3087000	rs1463055	hCV29819064	rs6698079	0.51	0.532906869	0.8488
  hCV3087000	rs1463055	hCV2987250	rs301810	0.51	0.532906869	0.7843
  hCV3087000	rs1463055	hCV29873524	rs7533113	0.51	0.532906869	0.7112
  hCV3087000	rs1463055	hCV29873526	rs6697997	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV29945430	rs7517436	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV30035535	rs7518204	0.51	0.532906869	0.7101
  hCV3087000	rs1463055	hCV30125699	rs4581300	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV30143725	rs6690050	0.51	0.532906869	0.8248
  hCV3087000	rs1463055	hCV30467730	rs6702457	0.51	0.532906869	0.8248
  hCV3087000	rs1463055	hCV3086930	rs6658881	0.51	0.532906869	0.815
  hCV3087000	rs1463055	hCV3086932	rs7533442	0.51	0.532906869	0.815
  hCV3087000	rs1463055	hCV3086950	rs4908771	0.51	0.532906869	0.8248
  hCV3087000	rs1463055	hCV3086961	rs6703577	0.51	0.532906869	0.8759
  hCV3087000	rs1463055	hCV3086971	rs6679948	0.51	0.532906869	0.8824
  hCV3087000	rs1463055	hCV3086972	rs6688329	0.51	0.532906869	0.8759
  hCV3087000	rs1463055	hCV3086998	rs7530863	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV3087003	rs6577500	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV3087015	rs11121198	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV3087016	rs2297867	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV32055284	rs12079653	0.51	0.532906869	0.6985
  hCV3087000	rs1463055	hCV32055470	rs6577506	0.51	0.532906869	0.8759
  hCV3087000	rs1463055	hCV32055474	rs10864359	0.51	0.532906869	0.8759
  hCV3087000	rs1463055	hCV32055477	rs10779705	0.51	0.532906869	0.8824
  hCV3087000	rs1463055	hCV32055527	rs10864364	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV32055548	rs11121197	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV32055579	rs6577522	0.51	0.532906869	0.7109
  hCV3087000	rs1463055	hCV32055595	rs6577524	0.51	0.532906869	0.7112
  hCV3087000	rs1463055	hCV32055596	rs6577525	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV32055625	rs6678590	0.51	0.532906869	0.6074
  hCV3087000	rs1463055	hCV32055637	rs6577532	0.51	0.532906869	0.6408
  hCV3087000	rs1463055	hCV32055677	rs10864355	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV529178	rs301811	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV529182	rs301800	0.51	0.532906869	0.7545
  hCV3087000	rs1463055	hCV597227	rs301809	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV597229	rs301785	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV877241	rs301788	0.51	0.532906869	0.6996
  hCV3087000	rs1463055	hCV8823713	rs1472228	0.51	0.532906869	0.6952
  hCV3087000	rs1463055	hCV8824288	rs910582	0.51	0.532906869	1
  hCV3087000	rs1463055	hCV8824394	rs1443929	0.51	0.532906869	0.6996
  hCV3087000	rs1463055	hCV8824424	rs1058790	0.51	0.532906869	0.7672
  hCV3087000	rs1463055	hCV8824425	rs1058791	0.51	0.532906869	0.754
  hCV3087000	rs1463055	hCV8881145	rs1038008	0.51	0.532906869	0.8824
  hCV3087000	rs1463055	hCV8881146	rs1463054	0.51	0.532906869	0.8271
  hCV3087000	rs1463055	hCV8881157	rs1535158	0.51	0.532906869	0.8824
  hCV3087000	rs1463055	hCV8881161	rs926951	0.51	0.532906869	1
  hCV3087003	rs6577500	hCV27958354	rs4908762	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV29873526	rs6697997	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV30125699	rs4581300	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV3086998	rs7530863	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV3087000	rs1463055	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV3087015	rs11121198	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV3087016	rs2297867	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV32055548	rs11121197	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV32055677	rs10864355	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV529178	rs301811	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV597227	rs301809	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV597229	rs301785	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV8824288	rs910582	0.51	0.967969018	1
  hCV3087003	rs6577500	hCV8881161	rs926951	0.51	0.967969018	1
  hCV3087008	rs12136689	hCV11675387	rs2120461	0.51	0.694720473	0.7177
  hCV3087008	rs12136689	hCV1265821	rs6577489	0.51	0.694720473	0.9622
  hCV3087008	rs12136689	hCV1265845	rs4908501	0.51	0.694720473	0.9607
  hCV3087008	rs12136689	hCV1417732	rs12128827	0.51	0.694720473	0.8134
  hCV3087008	rs12136689	hCV2943852	rs301795	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2958030	rs3765971	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2958031	rs2252865	0.51	0.694720473	0.7735
  hCV3087008	rs12136689	hCV2966430	rs2708633	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2966432	rs6678140	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2966435	rs894875	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2987217	rs301791	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2987218	rs301790	0.51	0.694720473	0.7225
  hCV3087008	rs12136689	hCV2987219	rs301789	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2987237	rs172531	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV2987238	rs301801	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV3086955	rs4908769	0.51	0.694720473	0.9612
  hCV3087008	rs12136689	hCV32055281	rs10779702	0.51	0.694720473	0.7735
  hCV3087008	rs12136689	hCV32055303	rs2784736	0.51	0.694720473	0.7018
  hCV3087008	rs12136689	hCV32055534	rs12125525	0.51	0.694720473	0.8589
  hCV3087008	rs12136689	hCV32055581	rs12123076	0.51	0.694720473	0.7789
  hCV3087008	rs12136689	hCV32055778	rs6577497	0.51	0.694720473	0.8349
  hCV3087008	rs12136689	hCV8823613	rs953043	0.51	0.694720473	0.8852
  hCV3087008	rs12136689	hCV8824315	rs302719	0.51	0.694720473	0.7018
  hCV3087015	rs11121198	hCV11398434	rs1812457	0.51	0.534576608	0.8824
  hCV3087015	rs11121198	hCV11398437	rs1817367	0.51	0.534576608	0.8638
  hCV3087015	rs11121198	hCV11675962	rs10746481	0.51	0.534576608	0.8248
  hCV3087015	rs11121198	hCV1188731	rs4908514	0.51	0.534576608	0.7112
  hCV3087015	rs11121198	hCV1188735	rs10864366	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV15882429	rs2289732	0.51	0.534576608	0.7153
  hCV3087015	rs11121198	hCV25996298	rs7535752	0.51	0.534576608	0.5809
  hCV3087015	rs11121198	hCV27157507	rs6664000	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV27157524	rs6577531	0.51	0.534576608	0.6596
  hCV3087015	rs11121198	hCV2741759	rs11121179	0.51	0.534576608	0.6996
  hCV3087015	rs11121198	hCV27474399	rs3753275	0.51	0.534576608	0.5827
  hCV3087015	rs11121198	hCV27884601	rs4908776	0.51	0.534576608	0.7103
  hCV3087015	rs11121198	hCV27958354	rs4908762	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV28023091	rs4908773	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV29368919	rs4908513	0.51	0.534576608	0.7112
  hCV3087015	rs11121198	hCV2943451	rs902355	0.51	0.534576608	0.7442
  hCV3087015	rs11121198	hCV2943853	rs301793	0.51	0.534576608	0.7153
  hCV3087015	rs11121198	hCV2966436	rs11121174	0.51	0.534576608	0.7153
  hCV3087015	rs11121198	hCV2966437	rs11580417	0.51	0.534576608	0.7153
  hCV3087015	rs11121198	hCV2966441	rs6684863	0.51	0.534576608	0.7153
  hCV3087015	rs11121198	hCV2966444	rs11121171	0.51	0.534576608	0.7672
  hCV3087015	rs11121198	hCV29819064	rs6698079	0.51	0.534576608	0.8488
  hCV3087015	rs11121198	hCV2987250	rs301810	0.51	0.534576608	0.8909
  hCV3087015	rs11121198	hCV29873524	rs7533113	0.51	0.534576608	0.7112
  hCV3087015	rs11121198	hCV29873526	rs6697997	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV29945430	rs7517436	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV30035535	rs7518204	0.51	0.534576608	0.7101
  hCV3087015	rs11121198	hCV30125699	rs4581300	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV30143725	rs6690050	0.51	0.534576608	0.8248
  hCV3087015	rs11121198	hCV30467730	rs6702457	0.51	0.534576608	0.8248
  hCV3087015	rs11121198	hCV3086930	rs6658881	0.51	0.534576608	0.815
  hCV3087015	rs11121198	hCV3086932	rs7533442	0.51	0.534576608	0.815
  hCV3087015	rs11121198	hCV3086950	rs4908771	0.51	0.534576608	0.8248
  hCV3087015	rs11121198	hCV3086961	rs6703577	0.51	0.534576608	0.8759
  hCV3087015	rs11121198	hCV3086971	rs6679948	0.51	0.534576608	0.8824
  hCV3087015	rs11121198	hCV3086972	rs6688329	0.51	0.534576608	0.8759
  hCV3087015	rs11121198	hCV3086998	rs7530863	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV3087000	rs1463055	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV3087003	rs6577500	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV3087016	rs2297867	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV32055284	rs12079653	0.51	0.534576608	0.6985
  hCV3087015	rs11121198	hCV32055470	rs6577506	0.51	0.534576608	0.8759
  hCV3087015	rs11121198	hCV32055474	rs10864359	0.51	0.534576608	0.8759
  hCV3087015	rs11121198	hCV32055477	rs10779705	0.51	0.534576608	0.8824
  hCV3087015	rs11121198	hCV32055527	rs10864364	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV32055548	rs11121197	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV32055579	rs6577522	0.51	0.534576608	0.7109
  hCV3087015	rs11121198	hCV32055595	rs6577524	0.51	0.534576608	0.7112
  hCV3087015	rs11121198	hCV32055596	rs6577525	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV32055625	rs6678590	0.51	0.534576608	0.6074
  hCV3087015	rs11121198	hCV32055637	rs6577532	0.51	0.534576608	0.6408
  hCV3087015	rs11121198	hCV32055677	rs10864355	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV529178	rs301811	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV529182	rs301800	0.51	0.534576608	0.7545
  hCV3087015	rs11121198	hCV597227	rs301809	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV597229	rs301785	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV877241	rs301788	0.51	0.534576608	0.6996
  hCV3087015	rs11121198	hCV8823713	rs1472228	0.51	0.534576608	0.6952
  hCV3087015	rs11121198	hCV8824288	rs910582	0.51	0.534576608	1
  hCV3087015	rs11121198	hCV8824394	rs1443929	0.51	0.534576608	0.6996
  hCV3087015	rs11121198	hCV8824424	rs1058790	0.51	0.534576608	0.7672
  hCV3087015	rs11121198	hCV8824425	rs1058791	0.51	0.534576608	0.754
  hCV3087015	rs11121198	hCV8881145	rs1038008	0.51	0.534576608	0.8824
  hCV3087015	rs11121198	hCV8881146	rs1463054	0.51	0.534576608	0.8271
  hCV3087015	rs11121198	hCV8881157	rs1535158	0.51	0.534576608	0.8824
  hCV3087015	rs11121198	hCV8881161	rs926951	0.51	0.534576608	1
  hCV3087016	rs2297867	hCV27958354	rs4908762	0.51	0.936425384	0.9694
  hCV3087016	rs2297867	hCV29873526	rs6697997	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV3086998	rs7530863	0.51	0.936425384	0.9694
  hCV3087016	rs2297867	hCV3087000	rs1463055	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV3087003	rs6577500	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV3087015	rs11121198	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV32055548	rs11121197	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV32055677	rs10864355	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV529178	rs301811	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV597227	rs301809	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV597229	rs301785	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV8824288	rs910582	0.51	0.936425384	1
  hCV3087016	rs2297867	hCV8881161	rs926951	0.51	0.936425384	0.9694
  hCV31145250	rs10889353	hCV11864156	rs10889334	0.51	0.9	1
  hCV31145250	rs10889353	hCV11864162	rs1167998	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV11865171	rs11208004	0.51	0.9	1
  hCV31145250	rs10889353	hCV11865185	rs10789117	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV11865201	rs10159255	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV12103105	rs1184865	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV12103127	rs1979722	0.51	0.9	0.9789
  hCV31145250	rs10889353	hCV12103499	rs2029763	0.51	0.9	1
  hCV31145250	rs10889353	hCV12103502	rs1168023	0.51	0.9	0.958
  hCV31145250	rs10889353	hCV1236535	rs1168042	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV149783	rs1168045	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV16214290	rs2366638	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV1778957	rs3913007	0.51	0.9	1
  hCV31145250	rs10889353	hCV1778958	rs634341	0.51	0.9	0.9558
  hCV31145250	rs10889353	hCV1778963	rs10158897	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV1778964	rs659656	0.51	0.9	1
  hCV31145250	rs10889353	hCV1778965	rs637723	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV1918028	rs10157265	0.51	0.9	0.958
  hCV31145250	rs10889353	hCV1918041	rs4587594	0.51	0.9	1
  hCV31145250	rs10889353	hCV1918054	rs10889347	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV2015148	rs11208007	0.51	0.9	0.9032
  hCV31145250	rs10889353	hCV25971202	rs10889335	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV26412183	rs1748199	0.51	0.9	0.9577
  hCV31145250	rs10889353	hCV26412184	rs11207990	0.51	0.9	0.9521
  hCV31145250	rs10889353	hCV27320451	rs4350231	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV27320465	rs641540	0.51	0.9	0.9586
  hCV31145250	rs10889353	hCV29103721	rs6678483	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV29103722	rs6675401	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV29103723	rs4329540	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV29647381	rs6690733	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV29749081	rs10493322	0.51	0.9	1
  hCV31145250	rs10889353	hCV30224093	rs7539035	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV31145255	rs11208000	0.51	0.9	0.9551
  hCV31145250	rs10889353	hCV31145262	rs10889352	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145264	rs10789119	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145266	rs10789118	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145267	rs11485618	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145269	rs6587980	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV31145277	rs10889350	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV31145279	rs10889349	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV31145282	rs11207997	0.51	0.9	0.9169
  hCV31145250	rs10889353	hCV31145290	rs12042319	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145291	rs11207995	0.51	0.9	0.9789
  hCV31145250	rs10889353	hCV31145298	rs11207992	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145302	rs12116574	0.51	0.9	1
  hCV31145250	rs10889353	hCV31145332	rs11207981	0.51	0.9	0.9538
  hCV31145250	rs10889353	hCV3122390	rs1748200	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV316299	rs1168026	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV316303	rs1168031	0.51	0.9	0.9586
  hCV31145250	rs10889353	hCV32220452	rs12090886	0.51	0.9	1
  hCV31145250	rs10889353	hCV32220453	rs10889337	0.51	0.9	0.9585
  hCV31145250	rs10889353	hCV32220467	rs10889333	0.51	0.9	1
  hCV31145250	rs10889353	hCV32220469	rs10889332	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV32220470	rs11207974	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV32220491	rs11577840	0.51	0.9	0.9586
  hCV31145250	rs10889353	hCV32220495	rs11207969	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV408090	rs1183260	0.51	0.9	0.9566
  hCV31145250	rs10889353	hCV445207	rs1627591	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV71419	rs2131925	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV857102	rs624660	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV857103	rs636497	0.51	0.9	0.9577
  hCV31145250	rs10889353	hCV857104	rs636523	0.51	0.9	1
  hCV31145250	rs10889353	hCV857108	rs597078	0.51	0.9	0.958
  hCV31145250	rs10889353	hCV857109	rs597470	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV857110	rs583609	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV857121	rs642845	0.51	0.9	0.958
  hCV31145250	rs10889353	hCV857122	rs656297	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV857123	rs638305	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV857127	rs631106	0.51	0.9	0.9577
  hCV31145250	rs10889353	hCV9508668	rs1781195	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV9581062	rs998403	0.51	0.9	1
  hCV31145250	rs10889353	hCV9581570	rs1168036	0.51	0.9	1
  hCV31145250	rs10889353	hCV9581571	rs1002687	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9581580	rs1168032	0.51	0.9	0.958
  hCV31145250	rs10889353	hCV9581581	rs1168030	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9581590	rs1168018	0.51	0.9	0.9789
  hCV31145250	rs10889353	hCV9581606	rs1168022	0.51	0.9	0.9558
  hCV31145250	rs10889353	hCV9581615	rs1748201	0.51	0.9	0.9789
  hCV31145250	rs10889353	hCV9581635	rs1748195	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV9581636	rs3850634	0.51	0.9	1
  hCV31145250	rs10889353	hCV9581680	rs1748197	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9581691	rs1570694	0.51	0.9	1
  hCV31145250	rs10889353	hCV9583244	rs783291	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9588770	rs1007205	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9588793	rs1168009	0.51	0.9	0.9365
  hCV31145250	rs10889353	hCV9588794	rs1168010	0.51	0.9	0.936
  hCV31145250	rs10889353	hCV9588829	rs1781212	0.51	0.9	0.959
  hCV31145250	rs10889353	hCV9588850	rs1168013	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV9588862	rs995000	0.51	0.9	1
  hCV31145250	rs10889353	hCV9588875	rs1168086	0.51	0.9	0.9551
  hCV31145250	rs10889353	hCV9588886	rs1168089	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV9588930	rs1168099	0.51	0.9	0.979
  hCV31145250	rs10889353	hCV9588985	rs1168124	0.51	0.9	0.959
  hCV31145250	rs10889353	hDV75176134	rs1781221	0.51	0.9	0.959
  hCV31161091	rs3127573	hCV16149755	rs2183470	0.51	0.665154887	0.776
  hCV31161091	rs3127573	hCV27397381	rs3120149	0.51	0.665154887	0.7457
  hCV31161091	rs3127573	hCV27403525	rs3119309	0.51	0.665154887	0.9549
  hCV31161091	rs3127573	hCV27459536	rs3119310	0.51	0.665154887	1
  hCV31161091	rs3127573	hCV27460260	rs3119311	0.51	0.665154887	0.9549
  hCV31161091	rs3127573	hCV27461119	rs3125056	0.51	0.665154887	0.7
  hCV31161091	rs3127573	hCV27462007	rs3127578	0.51	0.665154887	1
  hCV31161091	rs3127573	hCV27464241	rs3125052	0.51	0.665154887	0.776
  hCV31161091	rs3127573	hCV27464790	rs3127591	0.51	0.665154887	0.7283
  hCV31161091	rs3127573	hCV27517953	rs3798156	0.51	0.665154887	0.6692
  hCV31161091	rs3127573	hCV30977817	rs3106168	0.51	0.665154887	0.7755
  hCV31161091	rs3127573	hCV30977839	rs3120140	0.51	0.665154887	0.8656
  hCV31161091	rs3127573	hCV3b977855	rs3103350	0.51	0.665154887	0.776
  hCV31161091	rs3127573	hCV30977859	rs12209517	0.51	0.665154887	0.8649
  hCV31161091	rs3127573	hCV3111820	rs3127572	0.51	0.665154887	1
  hCV31161091	rs3127573	hCV31605072	rs12206585	0.51	0.665154887	0.7457
  hCV31161091	rs3127573	hCV31605081	rs12203303	0.51	0.665154887	0.7833
  hCV31161091	rs3127573	hDV71058825	rs7757336	0.51	0.665154887	0.6683
  hCV31161091	rs3127573	hDV71669191	rs3127586	0.51	0.665154887	0.8397
  hCV31161091	rs3127573	hDV71967259	rs7756836	0.51	0.665154887	0.9549
  hCV31161091	rs3127573	hDV75428625	rs3106167	0.51	0.665154887	0.776
  hCV31161091	rs3127573	hDV75428626	rs3106170	0.51	0.665154887	0.7452
  hCV31161091	rs3127573	hDV75428628	rs3106172	0.51	0.665154887	0.816
  hCV31161091	rs3127573	hDV75431938	rs3120151	0.51	0.665154887	0.776
  hCV31161091	rs3127573	hDV75433616	rs3125049	0.51	0.665154887	0.72
  hCV31237961	rs11950562	hCV26479157	rs2631360	0.51	0.9	1
  hCV31237961	rs11950562	hCV28006893	rs4705938	0.51	0.9	1
  hCV31237961	rs11950562	hCV29828916	rs10058074	0.51	0.9	1
  hCV31237961	rs11950562	hDV70978086	rs17622208	0.51	0.9	1
  hCV3135085	rs10795446	hCV11453231	rs12764449	0.51	0.9	1
  hCV3135085	rs10795446	hCV26740575	rs12263745	0.51	0.9	0.9603
  hCV3135085	rs10795446	hCV2822668	rs10904880	0.51	0.9	0.9602
  hCV3135085	rs10795446	hCV2822671	rs7900434	0.51	0.9	0.9794
  hCV3135085	rs10795446	hCV2822672	rs7900428	0.51	0.9	0.9169
  hCV3135085	rs10795446	hCV2822673	rs7900190	0.51	0.9	0.9793
  hCV3135085	rs10795446	hCV3135082	rs7921322	0.51	0.9	1
  hCV3135085	rs10795446	hCV3135091	rs4748355	0.51	0.9	0.9598
  hCV31528409	rs7635061	hCV251046	rs4075158	0.51	0.9	1
  hCV31528409	rs7635061	hCV31746376	rs12494136	0.51	0.9	1
  hCV31528409	rs7635061	hCV439262	rs8179973	0.51	0.9	0.9109
  hCV31528409	rs7635061	hCV439263	rs8180032	0.51	0.9	0.9051
  hCV3168675	rs469930	hCV984679	rs467650	0.51	0.9	0.9781
  hCV3168675	rs469930	hCV984683	rs468238	0.51	0.9	1
  hCV3168675	rs469930	hCV984684	rs154197	0.51	0.9	1
  hCV3170445	rs272893	hCV1173593	rs274567	0.51	0.9	1
  hCV3170445	rs272893	hCV1173600	rs274562	0.51	0.9	1
  hCV3170445	rs272893	hCV1173605	rs274559	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV2390950	rs274546	0.51	0.9	0.9804
  hCV3170445	rs272893	hCV2390957	rs272894	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV26479192	rs272865	0.51	0.9	0.922
  hCV3170445	rs272893	hCV2843383	rs2631370	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV2843392	rs272884	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV2843394	rs272881	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV2843395	rs272879	0.51	0.9	0.96
  hCV3170445	rs272893	hCV2950035	rs419291	0.51	0.9	0.9804
  hCV3170445	rs272893	hCV3170430	rs270613	0.51	0.9	0.9408
  hCV3170445	rs272893	hCV3170440	rs270605	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3170442	rs273914	0.51	0.9	0.9097
  hCV3170445	rs272893	hCV3170446	rs272889	0.51	0.9	1
  hCV3170445	rs272893	hCV3170448	rs272886	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3170453	rs272875	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3170454	rs272874	0.51	0.9	1
  hCV3170445	rs272893	hCV3170461	rs272869	0.51	0.9	1
  hCV3170445	rs272893	hCV3170463	rs4705933	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3170466	rs272867	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3281569	rs272842	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV3281570	rs270602	0.51	0.9	1
  hCV3170445	rs272893	hCV559622	rs274561	0.51	0.9	1
  hCV3170445	rs272893	hCV559623	rs274560	0.51	0.9	1
  hCV3170445	rs272893	hCV559624	rs274558	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV559625	rs274557	0.51	0.9	0.9612
  hCV3170445	rs272893	hCV9157871	rs272860	0.51	0.9	0.9589
  hCV3170445	rs272893	hCV9158012	rs273913	0.51	0.9	0.9612
  hCV3170459	rs1050152	hCV15849790	rs2188962	0.51	0.9	0.9412
  hCV3170459	rs1050152	hCV2554569	rs11951091	0.51	0.9	0.9644
  hCV3170459	rs1050152	hCV2554615	rs2522057	0.51	0.9	0.9037
  hCV3170459	rs1050152	hCV2554620	rs2248116	0.51	0.9	0.9027
  hCV3170459	rs1050152	hCV31237908	rs12515180	0.51	0.9	0.9624
  hCV3170459	rs1050152	hCV31237910	rs12521868	0.51	0.9	0.9409
  hCV3170459	rs1050152	hCV3281563	rs11741255	0.51	0.9	0.9226
  hCV3170459	rs1050152	hDV70978119	rs17622378	0.51	0.9	0.9639
  hCV3201490	rs1321195	hCV103951	rs6455688	0.51	0.325832601	0.3951
  hCV3201490	rs1321195	hCV103952	rs6923877	0.51	0.325832601	0.3951
  hCV3201490	rs1321195	hCV11284288	rs9457946	0.51	0.325832601	0.3442
  hCV3201490	rs1321195	hCV11285578	rs6926458	0.51	0.325832601	0.6014
  hCV3201490	rs1321195	hCV11846435	rs6929299	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV1550871	rs9355295	0.51	0.325832601	0.3554
  hCV3201490	rs1321195	hCV15975022	rs2314852	0.51	0.325832601	0.3961
  hCV3201490	rs1321195	hCV207123	rs7771801	0.51	0.325832601	0.3429
  hCV3201490	rs1321195	hCV207127	rs7453899	0.51	0.325832601	0.3635
  hCV3201490	rs1321195	hCV207128	rs6455689	0.51	0.325832601	0.3635
  hCV3201490	rs1321195	hCV243055	rs10945682	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV249898	rs9456552	0.51	0.325832601	0.3355
  hCV3201490	rs1321195	hCV25927459	rs3798221	0.51	0.325832601	0.6526
  hCV3201490	rs1321195	hCV25929408	rs7765781	0.51	0.325832601	0.3554
  hCV3201490	rs1321195	hCV25929478	rs7765803	0.51	0.325832601	0.3635
  hCV3201490	rs1321195	hCV26272388	rs7770685	0.51	0.325832601	0.6129
  hCV3201490	rs1321195	hCV26272389	rs7760585	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV27422538	rs6940254	0.51	0.325832601	0.6
  hCV3201490	rs1321195	hCV27422546	rs7761377	0.51	0.325832601	0.3287
  hCV3201490	rs1321195	hCV27422554	rs6923917	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV27422556	rs9355814	0.51	0.325832601	0.3325
  hCV3201490	rs1321195	hCV27422557	rs9355813	0.51	0.325832601	0.3283
  hCV3201490	rs1321195	hCV27422565	rs13202636	0.51	0.325832601	0.6129
  hCV3201490	rs1321195	hCV29322781	rs6921516	0.51	0.325832601	0.3635
  hCV3201490	rs1321195	hCV29546641	rs9365171	0.51	0.325832601	0.3342
  hCV3201490	rs1321195	hCV29998162	rs9457943	0.51	0.325832601	0.3554
  hCV3201490	rs1321195	hCV31882494	rs12175867	0.51	0.325832601	0.6
  hCV3201490	rs1321195	hCV3201494	rs1367209	0.51	0.325832601	0.4687
  hCV3201490	rs1321195	hCV3201495	rs1367210	0.51	0.325832601	1
  hCV3201490	rs1321195	hCV3201497	rs1321196	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV8701273	rs783148	0.51	0.325832601	1
  hCV3201490	rs1321195	hCV8710161	rs1740428	0.51	0.325832601	0.3278
  hCV3201490	rs1321195	hCV8710162	rs1367211	0.51	0.325832601	0.4687
  hCV32055474	rs10864359	hCV11398434	rs1812457	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV11398437	rs1817367	0.51	0.5160794	0.8987
  hCV32055474	rs10864359	hCV11675962	rs10746481	0.51	0.5160794	0.9345
  hCV32055474	rs10864359	hCV1188731	rs4908514	0.51	0.5160794	0.7979
  hCV32055474	rs10864359	hCV1188735	rs10864366	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV15882429	rs2289732	0.51	0.5160794	0.5747
  hCV32055474	rs10864359	hCV15932991	rs2781067	0.51	0.5160794	0.5621
  hCV32055474	rs10864359	hCV27157507	rs6664000	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV27157524	rs6577531	0.51	0.5160794	0.7394
  hCV32055474	rs10864359	hCV2741759	rs11121179	0.51	0.5160794	0.5606
  hCV32055474	rs10864359	hCV27884601	rs4908776	0.51	0.5160794	0.7973
  hCV32055474	rs10864359	hCV27958354	rs4908762	0.51	0.5160794	0.8778
  hCV32055474	rs10864359	hCV28023091	rs4908773	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV29368919	rs4908513	0.51	0.5160794	0.7979
  hCV32055474	rs10864359	hCV2943451	rs902355	0.51	0.5160794	0.6535
  hCV32055474	rs10864359	hCV2943853	rs301793	0.51	0.5160794	0.5747
  hCV32055474	rs10864359	hCV2966436	rs11121174	0.51	0.5160794	0.5747
  hCV32055474	rs10864359	hCV2966437	rs11580417	0.51	0.5160794	0.5747
  hCV32055474	rs10864359	hCV2966441	rs6684863	0.51	0.5160794	0.5747
  hCV32055474	rs10864359	hCV2966444	rs11121171	0.51	0.5160794	0.6208
  hCV32055474	rs10864359	hCV29819064	rs6698079	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV2987250	rs301810	0.51	0.5160794	0.665
  hCV32055474	rs10864359	hCV29873524	rs7533113	0.51	0.5160794	0.7979
  hCV32055474	rs10864359	hCV29873526	rs6697997	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV29945430	rs7517436	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV30035535	rs7518204	0.51	0.5160794	0.7971
  hCV32055474	rs10864359	hCV30125699	rs4581300	0.51	0.5160794	0.8169
  hCV32055474	rs10864359	hCV30143725	rs6690050	0.51	0.5160794	0.9345
  hCV32055474	rs10864359	hCV30467730	rs6702457	0.51	0.5160794	0.9345
  hCV32055474	rs10864359	hCV3086930	rs6658881	0.51	0.5160794	0.85
  hCV32055474	rs10864359	hCV3086932	rs7533442	0.51	0.5160794	0.85
  hCV32055474	rs10864359	hCV3086950	rs4908771	0.51	0.5160794	0.9345
  hCV32055474	rs10864359	hCV3086961	rs6703577	0.51	0.5160794	0.9379
  hCV32055474	rs10864359	hCV3086971	rs6679948	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV3086972	rs6688329	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV3086998	rs7530863	0.51	0.5160794	0.8778
  hCV32055474	rs10864359	hCV3087000	rs1463055	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV3087003	rs6577500	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV3087015	rs11121198	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV3087016	rs2297867	0.51	0.5160794	0.85
  hCV32055474	rs10864359	hCV32055284	rs12079653	0.51	0.5160794	0.6676
  hCV32055474	rs10864359	hCV32055470	rs6577506	0.51	0.5160794	0.9379
  hCV32055474	rs10864359	hCV32055477	rs10779705	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV32055527	rs10864364	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV32055548	rs11121197	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV32055579	rs6577522	0.51	0.5160794	0.7977
  hCV32055474	rs10864359	hCV32055595	rs6577524	0.51	0.5160794	0.7979
  hCV32055474	rs10864359	hCV32055596	rs6577525	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV32055625	rs6678590	0.51	0.5160794	0.7419
  hCV32055474	rs10864359	hCV32055637	rs6577532	0.51	0.5160794	0.5364
  hCV32055474	rs10864359	hCV32055677	rs10864355	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV529178	rs301811	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV529182	rs301800	0.51	0.5160794	0.5869
  hCV32055474	rs10864359	hCV597227	rs301809	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV597229	rs301785	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV877241	rs301788	0.51	0.5160794	0.5606
  hCV32055474	rs10864359	hCV8823713	rs1472228	0.51	0.5160794	0.6717
  hCV32055474	rs10864359	hCV8824288	rs910582	0.51	0.5160794	0.8759
  hCV32055474	rs10864359	hCV8824394	rs1443929	0.51	0.5160794	0.5606
  hCV32055474	rs10864359	hCV8824424	rs1058790	0.51	0.5160794	0.6208
  hCV32055474	rs10864359	hCV8824425	rs1058791	0.51	0.5160794	0.5324
  hCV32055474	rs10864359	hCV8881145	rs1038008	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV8881146	rs1463054	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV8881157	rs1535158	0.51	0.5160794	1
  hCV32055474	rs10864359	hCV8881161	rs926951	0.51	0.5160794	0.8778
  hCV32055477	rs10779705	hCV11398434	rs1812457	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV11398437	rs1817367	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV11675962	rs10746481	0.51	0.519194102	0.9381
  hCV32055477	rs10779705	hCV1188731	rs4908514	0.51	0.519194102	0.8094
  hCV32055477	rs10779705	hCV1188735	rs10864366	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV15882429	rs2289732	0.51	0.519194102	0.5975
  hCV32055477	rs10779705	hCV15932991	rs2781067	0.51	0.519194102	0.5861
  hCV32055477	rs10779705	hCV27157507	rs6664000	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV27157524	rs6577531	0.51	0.519194102	0.7539
  hCV32055477	rs10779705	hCV2741759	rs11121179	0.51	0.519194102	0.5747
  hCV32055477	rs10779705	hCV27884601	rs4908776	0.51	0.519194102	0.8089
  hCV32055477	rs10779705	hCV27958354	rs4908762	0.51	0.519194102	0.8759
  hCV32055477	rs10779705	hCV28023091	rs4908773	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV29368919	rs4908513	0.51	0.519194102	0.8094
  hCV32055477	rs10779705	hCV2943451	rs902355	0.51	0.519194102	0.6736
  hCV32055477	rs10779705	hCV2943853	rs301793	0.51	0.519194102	0.5975
  hCV32055477	rs10779705	hCV2966436	rs11121174	0.51	0.519194102	0.5975
  hCV32055477	rs10779705	hCV2966437	rs11580417	0.51	0.519194102	0.5975
  hCV32055477	rs10779705	hCV2966441	rs6684863	0.51	0.519194102	0.5975
  hCV32055477	rs10779705	hCV2966444	rs11121171	0.51	0.519194102	0.6417
  hCV32055477	rs10779705	hCV29819064	rs6698079	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV2987250	rs301810	0.51	0.519194102	0.6812
  hCV32055477	rs10779705	hCV29873524	rs7533113	0.51	0.519194102	0.8094
  hCV32055477	rs10779705	hCV29873526	rs6697997	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV29945430	rs7517436	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV30035535	rs7518204	0.51	0.519194102	0.8087
  hCV32055477	rs10779705	hCV30125699	rs4581300	0.51	0.519194102	0.8759
  hCV32055477	rs10779705	hCV30143725	rs6690050	0.51	0.519194102	0.9381
  hCV32055477	rs10779705	hCV30467730	rs6702457	0.51	0.519194102	0.9381
  hCV32055477	rs10779705	hCV3086930	rs6658881	0.51	0.519194102	0.9345
  hCV32055477	rs10779705	hCV3086932	rs7533442	0.51	0.519194102	0.9345
  hCV32055477	rs10779705	hCV3086950	rs4908771	0.51	0.519194102	0.9381
  hCV32055477	rs10779705	hCV3086961	rs6703577	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV3086971	rs6679948	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV3086972	rs6688329	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV3086998	rs7530863	0.51	0.519194102	0.8759
  hCV32055477	rs10779705	hCV3087000	rs1463055	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV3087003	rs6577500	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV3087015	rs11121198	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV3087016	rs2297867	0.51	0.519194102	0.8759
  hCV32055477	rs10779705	hCV32055284	rs12079653	0.51	0.519194102	0.6858
  hCV32055477	rs10779705	hCV32055470	rs6577506	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV32055474	rs10864359	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV32055527	rs10864364	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV32055548	rs11121197	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV32055579	rs6577522	0.51	0.519194102	0.8092
  hCV32055477	rs10779705	hCV32055595	rs6577524	0.51	0.519194102	0.8094
  hCV32055477	rs10779705	hCV32055596	rs6577525	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV32055625	rs6678590	0.51	0.519194102	0.7684
  hCV32055477	rs10779705	hCV32055637	rs6577532	0.51	0.519194102	0.7394
  hCV32055477	rs10779705	hCV32055662	rs6677249	0.51	0.519194102	0.5758
  hCV32055477	rs10779705	hCV32055677	rs10864355	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV529178	rs301811	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV529182	rs301800	0.51	0.519194102	0.6217
  hCV32055477	rs10779705	hCV597227	rs301809	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV597229	rs301785	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV877241	rs301788	0.51	0.519194102	0.5747
  hCV32055477	rs10779705	hCV8823713	rs1472228	0.51	0.519194102	0.7979
  hCV32055477	rs10779705	hCV8824288	rs910582	0.51	0.519194102	0.8824
  hCV32055477	rs10779705	hCV8824394	rs1443929	0.51	0.519194102	0.5747
  hCV32055477	rs10779705	hCV8824424	rs1058790	0.51	0.519194102	0.6417
  hCV32055477	rs10779705	hCV8824425	rs1058791	0.51	0.519194102	0.62
  hCV32055477	rs10779705	hCV8881145	rs1038008	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV8881146	rs1463054	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV8881157	rs1535158	0.51	0.519194102	1
  hCV32055477	rs10779705	hCV8881161	rs926951	0.51	0.519194102	0.8759
  hCV32055527	rs10864364	hCV11398434	rs1812457	0.51	0.494565781	0.7979
  hCV32055527	rs10864364	hCV11398437	rs1817367	0.51	0.494565781	0.6548
  hCV32055527	rs10864364	hCV11675962	rs10746481	0.51	0.494565781	0.8704
  hCV32055527	rs10864364	hCV1188659	rs3820037	0.51	0.494565781	0.5447
  hCV32055527	rs10864364	hCV1188660	rs6660137	0.51	0.494565781	0.5538
  hCV32055527	rs10864364	hCV1188664	rs2765511	0.51	0.494565781	0.6126
  hCV32055527	rs10864364	hCV1188665	rs2781060	0.51	0.494565781	0.6354
  hCV32055527	rs10864364	hCV1188676	rs11121247	0.51	0.494565781	0.5538
  hCV32055527	rs10864364	hCV1188731	rs4908514	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV1188735	rs10864366	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV12040675	rs2038904	0.51	0.494565781	0.6126
  hCV32055527	rs10864364	hCV15882429	rs2289732	0.51	0.494565781	0.6247
  hCV32055527	rs10864364	hCV15932991	rs2781067	0.51	0.494565781	0.6188
  hCV32055527	rs10864364	hCV15932992	rs2781068	0.51	0.494565781	0.6121
  hCV32055527	rs10864364	hCV27157507	rs6664000	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV27157524	rs6577531	0.51	0.494565781	0.9314
  hCV32055527	rs10864364	hCV2741759	rs11121179	0.51	0.494565781	0.6713
  hCV32055527	rs10864364	hCV27474399	rs3753275	0.51	0.494565781	0.5807
  hCV32055527	rs10864364	hCV27884601	rs4908776	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV27958354	rs4908762	0.51	0.494565781	0.6717
  hCV32055527	rs10864364	hCV28023091	rs4908773	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV29368919	rs4908513	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV2943451	rs902355	0.51	0.494565781	0.7098
  hCV32055527	rs10864364	hCV2943853	rs301793	0.51	0.494565781	0.6247
  hCV32055527	rs10864364	hCV2966436	rs11121174	0.51	0.494565781	0.6247
  hCV32055527	rs10864364	hCV2966437	rs11580417	0.51	0.494565781	0.6247
  hCV32055527	rs10864364	hCV2966441	rs6684863	0.51	0.494565781	0.6247
  hCV32055527	rs10864364	hCV2966444	rs11121171	0.51	0.494565781	0.6727
  hCV32055527	rs10864364	hCV29819064	rs6698079	0.51	0.494565781	0.7458
  hCV32055527	rs10864364	hCV2987250	rs301810	0.51	0.494565781	0.5105
  hCV32055527	rs10864364	hCV29873524	rs7533113	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV29873526	rs6697997	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV29945430	rs7517436	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV30035535	rs7518204	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV30125699	rs4581300	0.51	0.494565781	0.6067
  hCV32055527	rs10864364	hCV30143725	rs6690050	0.51	0.494565781	0.7437
  hCV32055527	rs10864364	hCV30467730	rs6702457	0.51	0.494565781	0.8704
  hCV32055527	rs10864364	hCV3086930	rs6658881	0.51	0.494565781	0.8213
  hCV32055527	rs10864364	hCV3086932	rs7533442	0.51	0.494565781	0.8213
  hCV32055527	rs10864364	hCV3086950	rs4908771	0.51	0.494565781	0.8704
  hCV32055527	rs10864364	hCV3086961	rs6703577	0.51	0.494565781	0.7188
  hCV32055527	rs10864364	hCV3086971	rs6679948	0.51	0.494565781	0.7979
  hCV32055527	rs10864364	hCV3086972	rs6688329	0.51	0.494565781	0.8568
  hCV32055527	rs10864364	hCV3086998	rs7530863	0.51	0.494565781	0.6717
  hCV32055527	rs10864364	hCV3087000	rs1463055	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV3087003	rs6577500	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV3087015	rs11121198	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV3087016	rs2297867	0.51	0.494565781	0.6499
  hCV32055527	rs10864364	hCV32055284	rs12079653	0.51	0.494565781	0.6676
  hCV32055527	rs10864364	hCV32055470	rs6577506	0.51	0.494565781	0.7188
  hCV32055527	rs10864364	hCV32055474	rs10864359	0.51	0.494565781	0.6717
  hCV32055527	rs10864364	hCV32055477	rs10779705	0.51	0.494565781	0.7979
  hCV32055527	rs10864364	hCV32055548	rs11121197	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV32055579	rs6577522	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV32055595	rs6577524	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV32055596	rs6577525	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV32055625	rs6678590	0.51	0.494565781	0.8645
  hCV32055527	rs10864364	hCV32055637	rs6577532	0.51	0.494565781	0.8301
  hCV32055527	rs10864364	hCV32055662	rs6677249	0.51	0.494565781	0.645
  hCV32055527	rs10864364	hCV32055677	rs10864355	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV529178	rs301811	0.51	0.494565781	0.6949
  hCV32055527	rs10864364	hCV529182	rs301800	0.51	0.494565781	0.6998
  hCV32055527	rs10864364	hCV597227	rs301809	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV597229	rs301785	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV877241	rs301788	0.51	0.494565781	0.6713
  hCV32055527	rs10864364	hCV8823713	rs1472228	0.51	0.494565781	1
  hCV32055527	rs10864364	hCV8824244	rs1006950	0.51	0.494565781	0.574
  hCV32055527	rs10864364	hCV8824248	rs1543711	0.51	0.494565781	0.6126
  hCV32055527	rs10864364	hCV8824288	rs910582	0.51	0.494565781	0.6952
  hCV32055527	rs10864364	hCV8824394	rs1443929	0.51	0.494565781	0.6713
  hCV32055527	rs10864364	hCV8824424	rs1058790	0.51	0.494565781	0.6727
  hCV32055527	rs10864364	hCV8824425	rs1958791	0.51	0.494565781	0.6383
  hCV32055527	rs10864364	hCV8881145	rs1038008	0.51	0.494565781	0.7979
  hCV32055527	rs10864364	hCV8881146	rs1463054	0.51	0.494565781	0.8032
  hCV32055527	rs10864364	hCV8881157	rs1535158	0.51	0.494565781	0.7979
  hCV32055527	rs10864364	hCV8881161	rs926951	0.51	0.494565781	0.6717
  hCV32055595	rs6577524	hCV11398434	rs1812457	0.51	0.496166123	0.8094
  hCV32055595	rs6577524	hCV11398437	rs1817367	0.51	0.496166123	0.7755
  hCV32055595	rs6577524	hCV11675962	rs10746481	0.51	0.496166123	0.8774
  hCV32055595	rs6577524	hCV1188659	rs3820037	0.51	0.496166123	0.5968
  hCV32055595	rs6577524	hCV1188660	rs6660137	0.51	0.496166123	0.6126
  hCV32055595	rs6577524	hCV1188664	rs2765511	0.51	0.496166123	0.6312
  hCV32055595	rs6577524	hCV1188665	rs2781060	0.51	0.496166123	0.6541
  hCV32055595	rs6577524	hCV1188676	rs11121247	0.51	0.496166123	0.6126
  hCV32055595	rs6577524	hCV1188731	rs4908514	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV1188735	rs10864366	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV12040675	rs2038904	0.51	0.496166123	0.6312
  hCV32055595	rs6577524	hCV15882429	rs2289732	0.51	0.496166123	0.6452
  hCV32055595	rs6577524	hCV15932991	rs2781067	0.51	0.496166123	0.6396
  hCV32055595	rs6577524	hCV15932992	rs2781068	0.51	0.496166123	0.6308
  hCV32055595	rs6577524	hCV27157507	rs6664000	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV27157524	rs6577531	0.51	0.496166123	0.9353
  hCV32055595	rs6577524	hCV27157546	rs11811795	0.51	0.496166123	0.5453
  hCV32055595	rs6577524	hCV27157560	rs11121252	0.51	0.496166123	0.5135
  hCV32055595	rs6577524	hCV2741759	rs11121179	0.51	0.496166123	0.6247
  hCV32055595	rs6577524	hCV27884601	rs4908776	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV27958354	rs4908762	0.51	0.496166123	0.6952
  hCV32055595	rs6577524	hCV28023091	rs4908773	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV29368919	rs4908513	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV2943451	rs902355	0.51	0.496166123	0.7273
  hCV32055595	rs6577524	hCV2943853	rs301793	0.51	0.496166123	0.6452
  hCV32055595	rs6577524	hCV2966436	rs11121174	0.51	0.496166123	0.6452
  hCV32055595	rs6577524	hCV2966437	rs11580417	0.51	0.496166123	0.6452
  hCV32055595	rs6577524	hCV2966441	rs6684863	0.51	0.496166123	0.6452
  hCV32055595	rs6577524	hCV2966444	rs11121171	0.51	0.496166123	0.6911
  hCV32055595	rs6577524	hCV29819064	rs6698079	0.51	0.496166123	0.7479
  hCV32055595	rs6577524	hCV2987250	rs301810	0.51	0.496166123	0.6312
  hCV32055595	rs6577524	hCV29873524	rs7533113	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV29873526	rs6697997	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV29945430	rs7517436	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV30035535	rs7518204	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV30125699	rs4581300	0.51	0.496166123	0.6952
  hCV32055595	rs6577524	hCV30143725	rs6690050	0.51	0.496166123	0.7577
  hCV32055595	rs6577524	hCV30467730	rs6702457	0.51	0.496166123	0.8774
  hCV32055595	rs6577524	hCV3086930	rs6658881	0.51	0.496166123	0.8704
  hCV32055595	rs6577524	hCV3086932	rs7533442	0.51	0.496166123	0.8704
  hCV32055595	rs6577524	hCV3086950	rs4908771	0.51	0.496166123	0.8774
  hCV32055595	rs6577524	hCV3086961	rs6703577	0.51	0.496166123	0.7979
  hCV32055595	rs6577524	hCV3086971	rs6679948	0.51	0.496166123	0.8094
  hCV32055595	rs6577524	hCV3086972	rs6688329	0.51	0.496166123	0.8654
  hCV32055595	rs6577524	hCV3086998	rs7530863	0.51	0.496166123	0.6952
  hCV32055595	rs6577524	hCV3087000	rs1463055	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV3087003	rs6577500	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV3087015	rs11121198	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV3087016	rs2297867	0.51	0.496166123	0.6952
  hCV32055595	rs6577524	hCV32055284	rs12079653	0.51	0.496166123	0.6858
  hCV32055595	rs6577524	hCV32055470	rs6577506	0.51	0.496166123	0.7979
  hCV32055595	rs6577524	hCV32055474	rs10864359	0.51	0.496166123	0.7979
  hCV32055595	rs6577524	hCV32055477	rs10779705	0.51	0.496166123	0.8094
  hCV32055595	rs6577524	hCV32055527	rs10864364	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV32055548	rs11121197	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV32055579	rs6577522	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV32055596	rs6577525	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV32055625	rs6678590	0.51	0.496166123	0.879
  hCV32055595	rs6577524	hCV32055637	rs6577532	0.51	0.496166123	0.9314
  hCV32055595	rs6577524	hCV32055662	rs6677249	0.51	0.496166123	0.7437
  hCV32055595	rs6577524	hCV32055677	rs10864355	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV529178	rs301811	0.51	0.496166123	0.7109
  hCV32055595	rs6577524	hCV529182	rs301800	0.51	0.496166123	0.6732
  hCV32055595	rs6577524	hCV597227	rs301809	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV597229	rs301785	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV877241	rs301788	0.51	0.496166123	0.6247
  hCV32055595	rs6577524	hCV8823713	rs1472228	0.51	0.496166123	1
  hCV32055595	rs6577524	hCV8824241	rs1325920	0.51	0.496166123	0.5423
  hCV32055595	rs6577524	hCV8824244	rs1006950	0.51	0.496166123	0.6126
  hCV32055595	rs6577524	hCV8824248	rs1543711	0.51	0.496166123	0.6312
  hCV32055595	rs6577524	hCV8824288	rs910582	0.51	0.496166123	0.7112
  hCV32055595	rs6577524	hCV8824394	rs1443929	0.51	0.496166123	0.6247
  hCV32055595	rs6577524	hCV8824424	rs1058790	0.51	0.496166123	0.6911
  hCV32055595	rs6577524	hCV8824425	rs1058791	0.51	0.496166123	0.6721
  hCV32055595	rs6577524	hCV8881145	rs1038008	0.51	0.496166123	0.8094
  hCV32055595	rs6577524	hCV8881146	rs1463054	0.51	0.496166123	0.8042
  hCV32055595	rs6577524	hCV8881157	rs1535158	0.51	0.496166123	0.8094
  hCV32055595	rs6577524	hCV8881161	rs926951	0.51	0.496166123	0.6952
  hCV32055596	rs6577525	hCV11675962	rs10746481	0.51	0.868658647	0.8704
  hCV32055596	rs6577525	hCV1188731	rs4908514	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV1188735	rs10864366	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV27157507	rs6664000	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV27157524	rs6577531	0.51	0.868658647	0.9314
  hCV32055596	rs6577525	hCV27884601	rs4908776	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV28023091	rs4908773	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV29368919	rs4908513	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV29873524	rs7533113	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV29945430	rs7517436	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV30035535	rs7518204	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV30467730	rs6702457	0.51	0.868658647	0.8704
  hCV32055596	rs6577525	hCV3086950	rs4908771	0.51	0.868658647	0.8704
  hCV32055596	rs6577525	hCV32055527	rs10864364	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV32055579	rs6577522	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV32055595	rs6577524	0.51	0.868658647	1
  hCV32055596	rs6577525	hCV8823713	rs1472228	0.51	0.868658647	1
  hCV32055625	rs6678590	hCV11398434	rs1812457	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV11398437	rs1817367	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV11675962	rs10746481	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV1188659	rs3820037	0.51	0.498774246	0.6049
  hCV32055625	rs6678590	hCV1188660	rs6660137	0.51	0.498774246	0.6341
  hCV32055625	rs6678590	hCV1188664	rs2765511	0.51	0.498774246	0.6612
  hCV32055625	rs6678590	hCV1188665	rs2781060	0.51	0.498774246	0.7019
  .hCV32055625	rs6678590	hCV1188676	rs11121247	0.51	0.498774246	0.6341
  hCV32055625	rs6678590	hCV1188731	rs4908514	0.51	0.498774246	0.879
  hCV32055625	rs6678590	hCV1188735	rs10864366	0.51	0.498774246	0.8645
  hCV32055625	rs6678590	hCV12040675	rs2038904	0.51	0.498774246	0.6612
  hCV32055625	rs6678590	hCV15882429	rs2289732	0.51	0.498774246	0.6066
  hCV32055625	rs6678590	hCV15932991	rs2781067	0.51	0.498774246	0.7025
  hCV32055625	rs6678590	hCV15932992	rs2781068	0.51	0.498774246	0.6612
  hCV32055625	rs6678590	hCV27157507	rs6664000	0.51	0.498774246	0.8645
  hCV32055625	rs6678590	hCV27157524	rs6577531	0.51	0.498774246	1
  hCV32055625	rs6678590	hCV27157546	rs11811795	0.51	0.498774246	0.6341
  hCV32055625	rs6678590	hCV2741759	rs11121179	0.51	0.498774246	0.5689
  hCV32055625	rs6678590	hCV27884601	rs4908776	0.51	0.498774246	0.8788
  hCV32055625	rs6678590	hCV27958354	rs4908762	0.51	0.498774246	0.57
  hCV32055625	rs6678590	hCV28023091	rs4908773	0.51	0.498774246	0.8645
  hCV32055625	rs6678590	hCV29368919	rs4908513	0.51	0.498774246	0.879
  hCV32055625	rs6678590	hCV2943451	rs902355	0.51	0.498774246	0.7115
  hCV32055625	rs6678590	hCV2943853	rs301793	0.51	0.498774246	0.6066
  hCV32055625	rs6678590	hCV2966436	rs11121174	0.51	0.498774246	0.6066
  hCV32055625	rs6678590	hCV2966437	rs11580417	0.51	0.498774246	0.6066
  hCV32055625	rs6678590	hCV2966441	rs6684863	0.51	0.498774246	0.6066
  hCV32055625	rs6678590	hCV2966444	rs11121171	0.51	0.498774246	0.6793
  hCV32055625	rs6678590	hCV29819064	rs6698079	0.51	0.498774246	0.7125
  hCV32055625	rs6678590	hCV29873524	rs7533113	0.51	0.498774246	0.879
  hCV32055625	rs6678590	hCV29873526	rs6697997	0.51	0.498774246	0.6074
  hCV32055625	rs6678590	hCV29945430	rs7517436	0.51	0.498774246	0.8645
  hCV32055625	rs6678590	hCV30035535	rs7518204	0.51	0.498774246	1
  hCV32055625	rs6678590	hCV30125699	rs4581300	0.51	0.498774246	0.57
  hCV32055625	rs6678590	hCV30143725	rs6690050	0.51	0.498774246	0.6799
  hCV32055625	rs6678590	hCV30467730	rs6702457	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV3086930	rs6658881	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV3086932	rs7533442	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV3086950	rs4908771	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV3086961	rs6703577	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV3086971	rs6679948	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV3086972	rs6688329	0.51	0.498774246	0.878
  hCV32055625	rs6678590	hCV3086998	rs7530863	0.51	0.498774246	0.57
  hCV32055625	rs6678590	hCV3087000	rs1463055	0.51	0.498774246	0.6074
  hCV32055625	rs6678590	hCV3087003	rs6577500	0.51	0.498774246	0.6074
  hCV32055625	rs6678590	hCV3087015	rs11121198	0.51	0.498774246	0.6074
  hCV32055625	rs6678590	hCV3087016	rs2297867	0.51	0.498774246	0.57
  hCV32055625	rs6678590	hCV32055284	rs12079653	0.51	0.498774246	0.6752
  hCV32055625	rs6678590	hCV32055470	rs6577506	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV32055474	rs10864359	0.51	0.498774246	0.7419
  hCV32055625	rs6678590	hCV32055477	rs10779705	0.51	0.498774246	0.7684
  hCV32055625	rs6678590	hCV32055527	rs10864364	0.51	0.498774246	0.8645
  hCV32055625	rs6678590	hCV32055548	rs11121197	0.51	0.498774246	0.6074
  hCV32055625	rs6678590	hCV32055579	rs6577522	0.51	0.498774246	0.879
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  hCV32055625	rs6678590	hCV32055596	rs6577525	0.51	0.498774246	0.8645
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  hCV32055625	rs6678590	hCV32055662	rs6677249	0.51	0.498774246	0.878
  hCV32055625	rs6678590	hCV32055677	rs10864355	0.51	0.498774246	0.6074
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  hCV32055625	rs6678590	hCV8881145	rs1038008	0.51	0.498774246	0.7684
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  hCV435368	rs2812	hCV481442	rs1122800	0.51	0.9	0.9442
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  hCV461035	rs7746448	hCV29161723	rs7766969	0.51	0.9	0.9435
  hCV461035	rs7746448	hCV30028095	rs10456690	0.51	0.9	0.9075
  hCV461035	rs7746448	hCV30136303	rs6914527	0.51	0.9	0.9415
  hCV461035	rs7746448	hCV30225897	rs9357829	0.51	0.9	0.9309
  hCV461035	rs7746448	hCV358624	rs4715508	0.51	0.9	0.9616
  hCV472000	rs3002374	hCV114713	rs11145615	0.51	0.430305154	0.8909
  hCV472000	rs3002374	hCV11760420	rs2498435	0.51	0.430305154	0.9002
  hCV472000	rs3002374	hCV1463195	rs11145103	0.51	0.430305154	0.5214
  hCV472000	rs3002374	hCV15978136	rs3002375	0.51	0.430305154	1
  hCV472000	rs3002374	hCV15978147	rs2498420	0.51	0.430305154	0.9002
  hCV472000	rs3002374	hCV20899	rs4237276	0.51	0.430305154	0.8091
  hCV472000	rs3002374	hCV29033518	rs7021593	0.51	0.430305154	0.4946
  hCV472000	rs3002374	hCV29169220	rs4745688	0.51	0.430305154	0.8953
  hCV472000	rs3002374	hCV30442834	rs10481782	0.51	0.430305154	0.8903
  hCV472000	rs3002374	hCV320070	rs13286409	0.51	0.430305154	0.8094
  hCV472000	rs3002374	hCV446684	rs2252949	0.51	0.430305154	1
  hCV472000	rs3002374	hCV447339	rs2486450	0.51	0.430305154	0.8662
  hCV472000	rs3002374	hCV457907	rs3002376	0.51	0.430305154	0.9002
  hCV472000	rs3002374	hCV500457	rs7018554	0.51	0.430305154	0.9474
  hCV472000	rs3002374	hCV76127	rs9411192	0.51	0.430305154	0.9002
  hCV472000	rs3002374	hCV85712	rs946541	0.51	0.430305154	0.9474
  hCV487868	rs6439132	hCV11230071	rs12490685	0.51	0.9	1
  hCV487868	rs6439132	hCV26427875	rs6803892	0.51	0.9	1
  hCV487868	rs6439132	hCV29665677	rs7631797	0.51	0.9	1
  hCV487868	rs6439132	hCV30387127	rs7629705	0.51	0.9	0.9255
  hCV529178	rs301811	hCV11398434	rs1812457	0.51	0.536691312	0.8824
  hCV529178	rs301811	hCV11398437	rs1817367	0.51	0.536691312	0.8638
  hCV529178	rs301811	hCV11675962	rs10746481	0.51	0.536691312	0.8246
  hCV529178	rs301811	hCV1188731	rs4908514	0.51	0.536691312	0.7109
  hCV529178	rs301811	hCV1188735	rs10864366	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV15882429	rs2289732	0.51	0.536691312	0.7149
  hCV529178	rs301811	hCV25996298	rs7535752	0.51	0.536691312	0.58
  hCV529178	rs301811	hCV27157507	rs6664000	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV27157524	rs6577531	0.51	0.536691312	0.659
  hCV529178	rs301811	hCV2741759	rs11121179	0.51	0.536691312	0.6991
  hCV529178	rs301811	hCV27474399	rs3753275	0.51	0.536691312	0.5818
  hCV529178	rs301811	hCV27884601	rs4908776	0.51	0.536691312	0.7101
  hCV529178	rs301811	hCV27958354	rs4908762	0.51	0.536691312	1
  hCV529178	rs301811	hCV28023091	rs4908773	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV29368919	rs4908513	0.51	0.536691312	0.7109
  hCV529178	rs301811	hCV2943451	rs902355	0.51	0.536691312	0.7442
  hCV529178	rs301811	hCV2943853	rs301793	0.51	0.536691312	0.7149
  hCV529178	rs301811	hCV2966436	rs11121174	0.51	0.536691312	0.7149
  hCV529178	rs301811	hCV2966437	rs11580417	0.51	0.536691312	0.7149
  hCV529178	rs301811	hCV2966441	rs6684863	0.51	0.536691312	0.7149
  hCV529178	rs301811	hCV2966444	rs11121171	0.51	0.536691312	0.767
  hCV529178	rs301811	hCV29819064	rs6698079	0.51	0.536691312	0.8488
  hCV529178	rs301811	hCV2987250	rs301810	0.51	0.536691312	0.8909
  hCV529178	rs301811	hCV29873524	rs7533113	0.51	0.536691312	0.7109
  hCV529178	rs301811	hCV29873526	rs6697997	0.51	0.536691312	1
  hCV529178	rs301811	hCV29945430	rs7517436	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV30035535	rs7518204	0.51	0.536691312	0.7098
  hCV529178	rs301811	hCV30125699	rs4581300	0.51	0.536691312	1
  hCV529178	rs301811	hCV30143725	rs6690050	0.51	0.536691312	0.8246
  hCV529178	rs301811	hCV30467730	rs6702457	0.51	0.536691312	0.8246
  hCV529178	rs301811	hCV3086930	rs6658881	0.51	0.536691312	0.8149
  hCV529178	rs301811	hCV3086932	rs7533442	0.51	0.536691312	0.8149
  hCV529178	rs301811	hCV3086950	rs4908771	0.51	0.536691312	0.8246
  hCV529178	rs301811	hCV3086961	rs6703577	0.51	0.536691312	0.8759
  hCV529178	rs301811	hCV3086971	rs6679948	0.51	0.536691312	0.8824
  hCV529178	rs301811	hCV3086972	rs6688329	0.51	0.536691312	0.8759
  hCV529178	rs301811	hCV3086998	rs7530863	0.51	0.536691312	1
  hCV529178	rs301811	hCV3087000	rs1463055	0.51	0.536691312	1
  hCV529178	rs301811	hCV3087003	rs6577500	0.51	0.536691312	1
  hCV529178	rs301811	hCV3087015	rs11121198	0.51	0.536691312	1
  hCV529178	rs301811	hCV3087016	rs2297867	0.51	0.536691312	1
  hCV529178	rs301811	hCV32055284	rs12079653	0.51	0.536691312	0.6985
  hCV529178	rs301811	hCV32055470	rs6577506	0.51	0.536691312	0.8759
  hCV529178	rs301811	hCV32055474	rs10864359	0.51	0.536691312	0.8759
  hCV529178	rs301811	hCV32055477	rs10779705	0.51	0.536691312	0.8824
  hCV529178	rs301811	hCV32055527	rs10864364	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV32055548	rs11121197	0.51	0.536691312	1
  hCV529178	rs301811	hCV32055579	rs6577522	0.51	0.536691312	0.7106
  hCV529178	rs301811	hCV32055595	rs6577524	0.51	0.536691312	0.7109
  hCV529178	rs301811	hCV32055596	rs6577525	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV32055625	rs6678590	0.51	0.536691312	0.6074
  hCV529178	rs301811	hCV32055637	rs6577532	0.51	0.536691312	0.6401
  hCV529178	rs301811	hCV32055677	rs10864355	0.51	0.536691312	1
  hCV529178	rs301811	hCV529182	rs301800	0.51	0.536691312	0.7543
  hCV529178	rs301811	hCV597227	rs301809	0.51	0.536691312	1
  hCV529178	rs301811	hCV597229	rs301785	0.51	0.536691312	1
  hCV529178	rs301811	hCV877241	rs301788	0.51	0.536691312	0.6991
  hCV529178	rs301811	hCV8823713	rs1472228	0.51	0.536691312	0.6949
  hCV529178	rs301811	hCV8824288	rs910582	0.51	0.536691312	1
  hCV529178	rs301811	hCV8824394	rs1443929	0.51	0.536691312	0.6991
  hCV529178	rs301811	hCV8824424	rs1058790	0.51	0.536691312	0.767
  hCV529178	rs301811	hCV8824425	rs1058791	0.51	0.536691312	0.7538
  hCV529178	rs301811	hCV8881145	rs1038008	0.51	0.536691312	0.8824
  hCV529178	rs301811	hCV8881146	rs1463054	0.51	0.536691312	0.8271
  hCV529178	rs301811	hCV8881157	rs1535158	0.51	0.536691312	0.8824
  hCV529178	rs301811	hCV8881161	rs926951	0.51	0.536691312	1
  hCV529706	rs428785	hCV1129216	rs370850	0.51	0.9	0.9486
  hCV529706	rs428785	hCV1129217	rs416905	0.51	0.9	0.9486
  hCV529706	rs428785	hCV1129218	rs420742	0.51	0.9	0.9486
  hCV529706	rs428785	hCV11799502	rs392840	0.51	0.9	0.9486
  hCV529706	rs428785	hCV529701	rs422381	0.51	0.9	0.9523
  hCV529706	rs428785	hCV529703	rs451792	0.51	0.9	0.9523
  hCV529706	rs428785	hCV529708	rs445784	0.51	0.9	0.9507
  hCV537525	rs197943	hCV15885004	rs2277614	0.51	0.550075489	0.6606
  hCV537525	rs197943	hCV2275251	rs197927	0.51	0.550075489	1
  hCV537525	rs197943	hCV2275252	rs197928	0.51	0.550075489	1
  hCV537525	rs197943	hCV2960488	rs197909	0.51	0.550075489	1
  hCV537525	rs197943	hCV7451329	rs197938	0.51	0.550075489	1
  hCV549926	rs1057141	hCV16222565	rs2395269	0.51	0.9	0.921
  hCV549926	rs1057141	hCV27015215	rs2071482	0.51	0.9	0.9603
  hCV549926	rs1057141	hCV2961762	rs12529313	0.51	0.9	1
  hCV549926	rs1057141	hCV2961763	rs12527715	0.51	0.9	1
  hCV597227	rs301809	hCV11398434	rs1812457	0.51	0.533875411	0.8824
  hCV597227	rs301809	hCV11398437	rs1817367	0.51	0.533875411	0.8638
  hCV597227	rs301809	hCV11675962	rs10746481	0.51	0.533875411	0.8248
  hCV597227	rs301809	hCV1188731	rs4908514	0.51	0.533875411	0.7112
  hCV597227	rs301809	hCV1188735	rs10864366	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV15882429	rs2289732	0.51	0.533875411	0.7153
  hCV597227	rs301809	hCV25996298	rs7535752	0.51	0.533875411	0.5809
  hCV597227	rs301809	hCV27157507	rs6664000	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV27157524	rs6577531	0.51	0.533875411	0.6596
  hCV597227	rs301809	hCV2741759	rs11121179	0.51	0.533875411	0.6996
  hCV597227	rs301809	hCV27474399	rs3753275	0.51	0.533875411	0.5827
  hCV597227	rs301809	hCV27884601	rs4908776	0.51	0.533875411	0.7103
  hCV597227	rs301809	hCV27958354	rs4908762	0.51	0.533875411	1
  hCV597227	rs301809	hCV28023091	rs4908773	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV29368919	rs4908513	0.51	0.533875411	0.7112
  hCV597227	rs301809	hCV2943451	rs902355	0.51	0.533875411	0.7442
  hCV597227	rs301809	hCV2943853	rs301793	0.51	0.533875411	0.7153
  hCV597227	rs301809	hCV2966436	rs11121174	0.51	0.533875411	0.7153
  hCV597227	rs301809	hCV2966437	rs11580417	0.51	0.533875411	0.7153
  hCV597227	rs301809	hCV2966441	rs6684863	0.51	0.533875411	0.7153
  hCV597227	rs301809	hCV2966444	rs11121171	0.51	0.533875411	0.7672
  hCV597227	rs301809	hCV29819064	rs6698079	0.51	0.533875411	0.8488
  hCV597227	rs301809	hCV2987250	rs301810	0.51	0.533875411	0.8909
  hCV597227	rs301809	hCV29873524	rs7533113	0.51	0.533875411	0.7112
  hCV597227	rs301809	hCV29873526	rs6697997	0.51	0.533875411	1
  hCV597227	rs301809	hCV29945430	rs7517436	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV30035535	rs7518204	0.51	0.533875411	0.7101
  hCV597227	rs301809	hCV30125699	rs4581300	0.51	0.533875411	1
  hCV597227	rs301809	hCV30143725	rs6690050	0.51	0.533875411	0.8248
  hCV597227	rs301809	hCV30467730	rs6702457	0.51	0.533875411	0.8248
  hCV597227	rs301809	hCV3086930	rs6658881	0.51	0.533875411	0.815
  hCV597227	rs301809	hCV3086932	rs7533442	0.51	0.533875411	0.815
  hCV597227	rs301809	hCV3086950	rs4908771	0.51	0.533875411	0.8248
  hCV597227	rs301809	hCV3086961	rs6703577	0.51	0.533875411	0.8759
  hCV597227	rs301809	hCV3086971	rs6679948	0.51	0.533875411	0.8824
  hCV597227	rs301809	hCV3086972	rs6688329	0.51	0.533875411	0.8759
  hCV597227	rs301809	hCV3086998	rs7530863	0.51	0.533875411	1
  hCV597227	rs301809	hCV3087000	rs1463055	0.51	0.533875411	1
  hCV597227	rs301809	hCV3087003	rs6577500	0.51	0.533875411	1
  hCV597227	rs301809	hCV3087015	rs11121198	0.51	0.533875411	1
  hCV597227	rs301809	hCV3087016	rs2297867	0.51	0.533875411	1
  hCV597227	rs301809	hCV32055284	rs12079653	0.51	0.533875411	0.6985
  hCV597227	rs301809	hCV32055470	rs6577506	0.51	0.533875411	0.8759
  hCV597227	rs301809	hCV32055474	rs10864359	0.51	0.533875411	0.8759
  hCV597227	rs301809	hCV32055477	rs10779705	0.51	0.533875411	0.8824
  hCV597227	rs301809	hCV32055527	rs10864364	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV32055548	rs11121197	0.51	0.533875411	1
  hCV597227	rs301809	hCV32055579	rs6577522	0.51	0.533875411	0.7109
  hCV597227	rs301809	hCV32055595	rs6577524	0.51	0.533875411	0.7112
  hCV597227	rs301809	hCV32055596	rs6577525	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV32055625	rs6678590	0.51	0.533875411	0.6074
  hCV597227	rs301809	hCV32055637	rs6577532	0.51	0.533875411	0.6408
  hCV597227	rs301809	hCV32055677	rs10864355	0.51	0.533875411	1
  hCV597227	rs301809	hCV529178	rs301811	0.51	0.533875411	1
  hCV597227	rs301809	hCV529182	rs301800	0.51	0.533875411	0.7545
  hCV597227	rs301809	hCV597229	rs301785	0.51	0.533875411	1
  hCV597227	rs301809	hCV877241	rs301788	0.51	0.533875411	0.6996
  hCV597227	rs301809	hCV8823713	rs1472228	0.51	0.533875411	0.6952
  hCV597227	rs301809	hCV8824288	rs910582	0.51	0.533875411	1
  hCV597227	rs301809	hCV8824394	rs1443929	0.51	0.533875411	0.6996
  hCV597227	rs301809	hCV8824424	rs1058790	0.51	0.533875411	0.7672
  hCV597227	rs301809	hCV8824425	rs1058791	0.51	0.533875411	0.754
  hCV597227	rs301809	hCV8881145	rs1038008	0.51	0.533875411	0.8824
  hCV597227	rs301809	hCV8881146	rs1463054	0.51	0.533875411	0.8271
  hCV597227	rs301809	hCV8881157	rs1535158	0.51	0.533875411	0.8824
  hCV597227	rs301809	hCV8881161	rs926951	0.51	0.533875411	1
  hCV598677	rs5370	hCV15870027	rs2071943	0.51	0.9	0.9736
  hCV598677	rs5370	hCV7464888	rs1800543	0.51	0.9	0.9732
  hCV598677	rs5370	hCV7464890	rs1476046	0.51	0.9	0.9736
  hCV601946	rs524802	hCV11467059	rs472226	0.51	0.9	0.9624
  hCV601946	rs524802	hCV25994206	rs3745770	0.51	0.9	0.9307
  hCV601946	rs524802	hCV26697405	rs547483	0.51	0.9	0.9624
  hCV601946	rs524802	hCV26697407	rs496872	0.51	0.9	0.9649
  hCV601946	rs524802	hCV27493801	rs3745768	0.51	0.9	0.9307
  hCV601946	rs524802	hCV30209952	rs10403679	0.51	0.9	0.9604
  hCV601946	rs524802	hCV601938	rs519551	0.51	0.9	0.9649
  hCV601946	rs524802	hCV601939	rs565721	0.51	0.9	0.9649
  hCV601946	rs524802	hCV601940	rs474017	0.51	0.9	0.9624
  hCV601946	rs524802	hCV601941	rs569371	0.51	0.9	0.9604
  hCV601946	rs524802	hCV601945	rs528504	0.51	0.9	0.9604
  hCV601946	rs524802	hCV601954	rs513406	0.51	0.9	0.9649
  hCV601946	rs524802	hCV8712373	rs1667343	0.51	0.9	0.9639
  hCV601946	rs524802	hCV8712515	rs826304	0.51	0.9	0.9624
  hCV601946	rs524802	hCV8712596	rs826303	0.51	0.9	0.9649
  hCV601946	rs524802	hCV8712603	rs826296	0.51	0.9	0.9642
  hCV601946	rs524802	hDV70773633	rs16971873	0.51	0.9	0.9649
  hCV601961	rs568654	hCV11467027	rs826262	0.51	0.9	1
  hCV601961	rs568654	hCV32351622	rs519606	0.51	0.9	0.9649
  hCV601961	rs568654	hCV601959	rs540451	0.51	0.9	1
  hCV601961	rs568654	hCV601962	rs544543	0.51	0.9	1
  hCV601961	rs568654	hCV601964	rs505717	0.51	0.9	1
  hCV601961	rs568654	hCV601966	rs551717	0.51	0.9	1
  hCV601961	rs568654	hCV601969	rs510757	0.51	0.9	1
  hCV601961	rs568654	hCV601972	rs484001	0.51	0.9	1
  hCV601961	rs568654	hCV8712620	rs826290	0.51	0.9	1
  hCV601961	rs568654	hCV8712646	rs1644711	0.51	0.9	1
  hCV601962	rs544543	hCV11467027	rs826262	0.51	0.9	1
  hCV601962	rs544543	hCV32351622	rs519606	0.51	0.9	0.9658
  hCV601962	rs544543	hCV601959	rs540451	0.51	0.9	1
  hCV601962	rs544543	hCV601961	rs568654	0.51	0.9	1
  hCV601962	rs544543	hCV601964	rs505717	0.51	0.9	1
  hCV601962	rs544543	hCV601966	rs551717	0.51	0.9	1
  hCV601962	rs544543	hCV601969	rs510757	0.51	0.9	1
  hCV601962	rs544543	hCV601972	rs484001	0.51	0.9	1
  hCV601962	rs544543	hCV8712620	rs826290	0.51	0.9	1
  hCV601962	rs544543	hCV8712646	rs1644711	0.51	0.9	1
  hCV610861	rs636887	hCV8821402	rs1076052	0.51	0.9	1
  hCV621313	rs471364	hCV16053903	rs2616751	0.51	0.9	1
  hCV621313	rs471364	hCV27926761	rs3933785	0.51	0.9	1
  hCV621313	rs471364	hCV27993845	rs3933784	0.51	0.9	1
  hCV621313	rs471364	hCV28015592	rs4237138	0.51	0.9	1
  hCV621313	rs471364	hCV31935994	rs1475229	0.51	0.9	1
  hCV7442005	rs1538584	hCV11759640	rs7850573	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV11759644	rs6560584	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV11759645	rs7034303	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV11759647	rs7048937	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV11760387	rs2309422	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hCV11760421	rs12056979	0.51	0.495145847	0.6526
  hCV7442005	rs1538584	hCV11761216	rs7874888	0.51	0.495145847	0.6359
  hCV7442005	rs1538584	hCV11761223	rs2309426	0.51	0.495145847	0.6079
  hCV7442005	rs1538584	hCV11761237	rs4329331	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hCV11761239	rs4338173	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hCV11761245	rs7043149	0.51	0.495145847	1
  hCV7442005	rs1538584	hCV1844076	rs1339546	0.51	0.495145847	0.7161
  hCV7442005	rs1538584	hCV20896	rs2309424	0.51	0.495145847	0.7161
  hCV7442005	rs1538584	hCV25805877	rs3750549	0.51	0.495145847	0.6376
  hCV7442005	rs1538584	hCV26566188	rs4375066	0.51	0.495145847	0.6691
  hCV7442005	rs1538584	hCV26566190	rs3927676	0.51	0.495145847	0.6691
  hCV7442005	rs1538584	hCV26566432	rs4076288	0.51	0.495145847	0.8185
  hCV7442005	rs1538584	hCV26566437	rs4421408	0.51	0.495145847	0.6526
  hCV7442005	rs1538584	hCV26566445	rs4339703	0.51	0.495145847	0.8065
  hCV7442005	rs1538584	hCV27970553	rs5006364	0.51	0.495145847	0.8065
  hCV7442005	rs1538584	hCV27996874	rs4745701	0.51	0.495145847	0.9644
  hCV7442005	rs1538584	hCV29169289	rs6560585	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV29577088	rs9314865	0.51	0.495145847	0.7161
  hCV7442005	rs1538584	hCV29830130	rs10217168	0.51	0.495145847	0.7161
  hCV7442005	rs1538584	hCV30172680	rs10122932	0.51	0.495145847	0.6452
  hCV7442005	rs1538584	hCV30532761	rs10125494	0.51	0.495145847	0.6526
  hCV7442005	rs1538584	hCV31363642	rs7862404	0.51	0.495145847	0.6403
  hCV7442005	rs1538584	hCV31363652	rs10869961	0.51	0.495145847	0.6526
  hCV7442005	rs1538584	hCV31363664	rs10869975	0.51	0.495145847	0.6889
  hCV7442005	rs1538584	hCV31363697	rs7041781	0.51	0.495145847	0.6376
  hCV7442005	rs1538584	hCV31364135	rs10781440	0.51	0.495145847	0.6798
  hCV7442005	rs1538584	hCV31364138	rs7865373	0.51	0.495145847	0.6798
  hCV7442005	rs1538584	hCV31364140	rs7467352	0.51	0.495145847	0.6455
  hCV7442005	rs1538584	hCV31364141	rs11145460	0.51	0.495145847	0.6661
  hCV7442005	rs1538584	hCV446682	rs2309427	0.51	0.495145847	0.6359
  hCV7442005	rs1538584	hCV450641	rs10781456	0.51	0.495145847	0.6798
  hCV7442005	rs1538584	hCV453560	rs10869992	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hCV453561	rs10869993	0.51	0.495145847	0.6641
  hCV7442005	rs1538584	hCV453562	rs10869994	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hCV453563	rs10869997	0.51	0.495145847	0.678
  hCV7442005	rs1538584	hCV456556	rs4076287	0.51	0.495145847	0.6673
  hCV7442005	rs1538584	hCV463630	rs2486451	0.51	0.495145847	1
  hCV7442005	rs1538584	hCV500456	rs10869976	0.51	0.495145847	0.6857
  hCV7442005	rs1538584	hCV7441996	rs867346	0.51	0.495145847	0.6831
  hCV7442005	rs1538584	hCV7442003	rs884428	0.51	0.495145847	0.6691
  hCV7442005	rs1538584	hCV7442004	rs884429	0.51	0.495145847	0.6691
  hCV7442005	rs1538584	hCV7482544	rs1416738	0.51	0.495145847	0.6798
  hCV7442005	rs1538584	hDV70840481	rs17062237	0.51	0.495145847	0.6742
  hCV7442005	rs1538584	hDV71162544	rs1416739	0.51	0.495145847	0.6567
  hCV7442005	rs1538584	hDV81101901	rs4745650	0.51	0.495145847	0.6526
  hCV7443062	rs897453	hCV7443053	rs1108579	0.51	0.9	0.9298
  hCV7480314	rs3851799	hCV16192346	rs2316758	0.51	0.769799979	1
  hCV7480314	rs3851799	hCV2592673	rs4968286	0.51	0.769799979	0.788
  hCV7480314	rs3851799	hCV2592715	rs3851792	0.51	0.769799979	1
  hCV7480314	rs3851799	hCV26660327	rs11869840	0.51	0.769799979	0.788
  hCV7480314	rs3851799	hCV27899058	rs4074249	0.51	0.769799979	0.8511
  hCV7480314	rs3851799	hCV29195255	rs8068715	0.51	0.769799979	1
  hCV7480314	rs3851799	hCV29195260	rs3851798	0.51	0.769799979	1
  hCV7480314	rs3851799	hCV2959464	rs3760377	0.51	0.769799979	0.788
  hCV7480314	rs3851799	hCV2959466	rs6504622	0.51	0.769799979	0.788
  hCV7480314	rs3851799	hCV2960484	rs11653838	0.51	0.769799979	0.8511
  hCV7480314	rs3851799	hCV30299603	rs9889762	0.51	0.769799979	0.788
  hCV7480314	rs3851799	hCV31479403	rs11079750	0.51	0.769799979	0.8526
  hCV7480314	rs3851799	hCV341736	rs11653589	0.51	0.769799979	1
  hCV7480314	rs3851799	hCV348972	rs11079747	0.51	0.769799979	0.9616
  hCV7480314	rs3851799	hCV473201	rs12950699	0.51	0.769799979	0.8598
  hCV7480314	rs3851799	hCV498633	rs4968304	0.51	0.769799979	0.8598
  hCV7480314	rs3851799	hCV9268384	rs7216950	0.51	0.769799979	0.8496
  hCV7490135	rs1805082	hCV12087046	rs1808579	0.51	0.9	0.9437
  hCV7490135	rs1805082	hCV16017395	rs2435307	0.51	0.9	0.9439
  hCV7490135	rs1805082	hCV16023276	rs2510340	0.51	0.9	0.931
  hCV7490135	rs1805082	hCV25620752	rs7239575	0.51	0.9	1
  hCV7490135	rs1805082	hCV27004508	rs2960578	0.51	0.9	0.9628
  hCV7490135	rs1805082	hCV2950793	rs1652343	0.51	0.9	0.9628
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  hCV7490135	rs1805082	hCV3203990	rs1429935	0.51	0.9	0.9624
  hCV7490135	rs1805082	hCV3203995	rs1367083	0.51	0.9	0.9623
  hCV7490135	rs1805082	hCV3203996	rs6507708	0.51	0.9	0.931
  hCV7490135	rs1805082	hCV3204000	rs891387	0.51	0.9	0.9628
  hCV7490135	rs1805082	hCV3204001	rs891386	0.51	0.9	0.9271
  hCV7490135	rs1805082	hCV3204007	rs2510344	0.51	0.9	1
  hCV7490135	rs1805082	hCV3204010	rs6507716	0.51	0.9	0.9812
  hCV7490135	rs1805082	hCV3204011	rs12964689	0.51	0.9	1
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  hCV7490135	rs1805082	hCV3204021	rs11663558	0.51	0.9	0.9271
  hCV7490135	rs1805082	hCV3204027	rs1623060	0.51	0.9	0.9628
  hCV7490135	rs1805082	hCV3204029	rs1652348	0.51	0.9	1
  hCV7490135	rs1805082	hCV3204038	rs1788783	0.51	0.9	0.9628
  hCV7490135	rs1805082	hCV7490108	rs1631685	0.51	0.9	0.9628
  hCV7490135	rs1805082	hCV7490208	rs1788817	0.51	0.9	0.9436
  hCV7490135	rs1805082	hDV77046157	rs4800493	0.51	0.9	0.931
  hCV7501549	rs1467412	hCV16230554	rs2426320	0.51	0.9	1
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  hCV7514870	rs1041981	hCV27463589	rs3130059	0.51	0.9	0.9621
  hCV7514870	rs1041981	hCV30139067	rs3093974	0.51	0.9	0.958
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  hCV7514870	rs1041981	hCV3273591	rs2071594	0.51	0.9	0.9791
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  hCV7514870	rs1041981	hCV3273612	rs11796	0.51	0.9	0.9791
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  hCV783138	rs6046	hCV50000100	rs561241	0.51	0.9	0.9234
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  hCV795441	rs401502	hCV795459	rs376008	0.51	0.9	1
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  hCV795442	rs375947	hCV795446	rs365179	0.51	0.9	0.9552
  hCV795442	rs375947	hCV795454	rs429774	0.51	0.9	0.9795
  hCV795442	rs375947	hCV795455	rs382634	0.51	0.9	0.9059
  hCV795442	rs375947	hCV795459	rs376008	0.51	0.9	1
  hCV795442	rs375947	hDV71612301	rs17852635	0.51	0.9	0.9795
  hCV818008	rs5918	hCV29197695	rs7214096	0.51	0.9	1
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  hCV8369472	rs1447351	hCV26158785	rs4406791	0.51	0.9	0.9649
  hCV8369472	rs1447351	hCV26158787	rs4753073	0.51	0.9	1
  hCV8369472	rs1447351	hCV27965689	rs4753072	0.51	0.9	1
  hCV8369472	rs1447351	hCV29662341	rs6483213	0.51	0.9	0.9643
  hCV8369472	rs1447351	hCV3256840	rs9666752	0.51	0.9	0.9649
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  hCV8369472	rs1447351	hCV3256849	rs1597023	0.51	0.9	0.963
  hCV8369472	rs1447351	hCV3256853	rs4611171	0.51	0.9	0.963
  hCV8369472	rs1447351	hCV8369473	rs1447350	0.51	0.9	1
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  hCV8379452	rs4908781	hCV11675982	rs1953827	0.51	0.494607042	0.4974
  hCV8379452	rs4908781	hCV11675985	rs12136766	0.51	0.494607042	0.4974
  hCV8379452	rs4908781	hCV1188706	rs2185205	0.51	0.494607042	0.8302
  hCV8379452	rs4908781	hCV1188726	rs6698830	0.51	0.494607042	0.7147
  hCV8379452	rs4908781	hCV1188747	rs4908511	0.51	0.494607042	0.7134
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  hCV8379452	rs4908781	hCV1265858	rs11121194	0.51	0.494607042	0.4974
  hCV8379452	rs4908781	hCV27157851	rs4480384	0.51	0.494607042	0.5249
  hCV8379452	rs4908781	hCV29368911	rs6577513	0.51	0.494607042	0.5458
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  hCV8379452	rs4908781	hCV29981708	rs7554486	0.51	0.494607042	0.5371
  hCV8379452	rs4908781	hCV30233466	rs7513880	0.51	0.494607042	0.7147
  hCV8379452	rs4908781	hCV30413939	rs6701331	0.51	0.494607042	0.4974
  hCV8379452	rs4908781	hCV30413946	rs7537982	0.51	0.494607042	0.5249
  hCV8379452	rs4908781	hCV3086941	rs7556169	0.51	0.494607042	0.526
  hCV8379452	rs4908781	hCV3086945	rs6695867	0.51	0.494607042	0.5543
  hCV8379452	rs4908781	hCV3086948	rs10864361	0.51	0.494607042	0.5552
  hCV8379452	rs4908781	hCV3b86949	rs11121212	0.51	0.494607042	0.5342
  hCV8379452	rs4908781	hCV3086954	rs1463053	0.51	0.494607042	0.526
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  hCV8379452	rs4908781	hCV3086959	rs7520025	0.51	0.494607042	0.5204
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  hCV8379452	rs4908781	hCV32055489	rs10864360	0.51	0.494607042	0.5342
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  hCV8379452	rs4908781	hCV32055554	rs12024032	0.51	0.494607042	0.7134
  hCV8379452	rs4908781	hCV32055587	rs10864367	0.51	0.494607042	0.7147
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  hCV8379452	rs4908781	hCV32392515	rs4908505	0.51	0.494607042	0.5552
  hCV8379452	rs4908781	hDV75072264	rs12403640	0.51	0.494607042	0.6803
  hCV8379452	rs4908781	hDV77058075	rs4908506	0.51	0.494607042	0.526
  hCV8420416	rs719909	hCV29251974	rs7905163	0.51	0.9	1
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  hCV8709053	rs4880	hCV16072287	rs2855116	0.51	0.9	0.9625
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  hCV8737990	rs419598	hCV11948077	rs16065	0.51	0.9	0.9557
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  hCV8737990	rs419598	hCV3133511	rs4251984	0.51	0.9	0.9557
  hCV8737990	rs419598	hCV3133512	rs4251985	0.51	0.9	0.9557
  hCV8737990	rs419598	hCV3133519	rs2853628	0.51	0.9	0.9432
  hCV8737990	rs419598	hCV32060324	rs4251967	0.51	0.9	1
  hCV8737990	rs419598	hCV3252471	rs444413	0.51	0.9	1
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  hCV8737990	rs419598	hCV8737960	rs440286	0.51	0.9	0.9537
  hCV8737990	rs419598	hCV8737965	rs431726	0.51	0.9	0.9547
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  hCV8737990	rs419598	hCV8737979	rs442710	0.51	0.9	1
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  hCV8737990	rs419598	hDV76981932	rs4251970	0.51	0.9	0.9556
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  hCV8784787	rs688976	hCV12020219	r5624601	0.51	0.9	1
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  hCV8784787	rs688976	hCV25610830	rs8176717	0.51	0.9	1
  hCV8784787	rs688976	hCV25610847	rs8176714	0.51	0.9	1
  hCV8784787	rs688976	hCV26744836	rs500428	0.51	0.9	0.9766
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  hCV8784787	rs688976	hCV30534973	rs626035	0.51	0.9	1
  hCV8784787	rs688976	hCV30661132	rs11244053	0.51	0.9	1
  hCV8784787	rs688976	hCV3183108	rs474279	0.51	0.9	1
  hCV8784787	rs688976	hCV3183120	rs574311	0.51	0.9	1
  hCV8784787	rs688976	hCV8784788	rs493211	0.51	0.9	0.9497
  hCV8784787	rs688976	hCV997885	rs641959	0.51	0.9	0.9129
  hCV8784787	rs688976	hCV997886	rs641943	0.51	0.9	0.9541
  hCV8784787	rs688976	hCV997887	rs514708	0.51	0.9	0.9541
  hCV8784787	rs688976	hCV997888	rs517414	0.51	0.9	1
  hCV8784787	rs688976	hCV997889	rs638756	0.51	0.9	0.9503
  hCV8784787	rs688976	hCV997893	rs547643	0.51	0.9	1
  hCV8784787	rs688976	hCV997897	rs549446	0.51	0.9	1
  hCV8784787	rs688976	hCV997902	rs574347	0.51	0.9	1
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  hCV8784787	rs688976	hCV997906	rs672316	0.51	0.9	0.9541
  hCV8784787	rs688976	hCV997925	rs552148	0.51	0.9	0.9767
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  hCV8785824	rs1412426	hCV11841945	rs10815370	0.51	0.9	0.93
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  hCV8785827	rs992969	hCV12096527	rs1888909	0.51	0.9	0.9767
  hCV8785827	rs992969	hCV12096531	rs928413	0.51	0.9	0.9767
  hCV8785827	rs992969	hCV16108911	rs2095044	0.51	0.9	0.9616
  hCV8785827	rs992969	hCV16225421	rs2381416	0.51	0.9	0.9252
  hCV8785827	rs992969	hCV2762168	rs3939286	0.51	0.9	1
  hCV8785827	rs992969	hCV31940459	rs7848215	0.51	0.9	0.9252
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  hCV8804621	rs1390938	hCV2716010	rs6586898	0.51	0.9	0.9759
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  hCV8804621	rs1390938	hCV8804626	rs988713	0.51	0.9	0.9756
  hCV8823713	rs1472228	hCV1188731	rs4908514	0.51	0.900026297	1
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  hCV8823713	rs1472228	hCV27157524	rs6577531	0.51	0.900026297	0.9314
  hCV8823713	rs1472228	hCV27884601	rs4908776	0.51	0.900026297	1
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  hCV8823713	rs1472228	hCV29945430	rs7517436	0.51	0.900026297	1
  hCV8823713	rs1472228	hCV30035535	rs7518204	0.51	0.900026297	1
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  hCV8824248	rs1543711	hCV1188659	rs3820037	0.51	0.867554387	1
  hCV8824248	rs1543711	hCV1188660	rs6660137	0.51	0.867554387	1
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  hCV8824394	rs1443929	hCV27474399	rs3753275	0.51	0.868495377	0.8913
  hCV8824394	rs1443929	hCV2943451	rs902355	0.51	0.868495377	0.9232
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  hCV8824394	rs1443929	hCV2966444	rs11121171	0.51	0.868495377	0.9345
  hCV8824394	rs1443929	hCV32055284	rs12079653	0.51	0.868495377	0.9336
  hCV8824394	rs1443929	hCV529182	rs301800	0.51	0.868495377	0.9634
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  hCV8824424	rs1058790	hCV15882429	rs2289732	0.51	0.899566528	0.9381
  hCV8824424	rs1058790	hCV2741759	rs11121179	0.51	0.899566528	0.9345
  hCV8824424	rs1058790	hCV2943451	rs902355	0.51	0.899566528	0.928
  hCV8824424	rs1058790	hCV2943853	rs301793	0.51	0.899566528	0.9381
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  hCV8824424	rs1058790	hCV877241	rs301788	0.51	0.899566528	0.9345
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  hCV8892418	rs901746	hCV11666937	rs7395581	0.51	0.9	0.9122
  hCV8892418	rs901746	hCV1301028	rs830085	0.51	0.9	0.978
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  hCV8892418	rs901746	hCV1301085	rs1375688	0.51	0.9	0.907
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  hCV8892418	rs901746	hCV27477935	rs3758673	0.51	0.9	0.9776
  hCV8892418	rs901746	hCV27484275	rs3781622	0.51	0.9	0.907
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  hCV8892418	rs901746	hCV30887894	rs4752824	0.51	0.9	0.9359
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  hCV8895373	rs1503185	hCV11665715	rs11039522	0.51	0.9	0.9186
  hCV8895373	rs1503185	hCV11665751	rs12576134	0.51	0.9	0.9133
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  hCV8895373	rs1503185	hCV288149	rs1566734	0.51	0.9	0.9564
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  hCV8895373	rs1503185	hCV31699653	rs11599936	0.51	0.9	0.9236
  hCV8895373	rs1503185	hCV440189	rs11600061	0.51	0.9	0.9278
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  hCV8901525	rs861539	hCV16012197	rs2403205	0.51	0.9	0.9808
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  hCV922535	rs748065	hCV29681450	rs4872494	0.51	0.9	0.9628
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  hCV9506149	rs1250259	hCV11734951	rs1250247	0.51	0.9	0.955
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  hCV9506149	rs1250259	hCV2110751	rs1250229	0.51	0.9	0.9111
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  hCV9581635	rs1748195	hCV11864162	rs1167998	0.51	0.9	0.9791
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  hCV9581635	rs1748195	hCV11855196	rs7555577	0.51	0.9	0.919
  hCV9581635	rs1748195	hCV11865201	rs10159255	0.51	0.9	0.958
  hCV9581635	rs1748195	hCV12103105	rs1184865	0.51	0.9	0.9791
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  hCV9581635	rs1748195	hCV1778957	rs3913007	0.51	0.9	0.979
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  hCV9581635	rs1748195	hCV1778961	rs630144	0.51	0.9	0.9164
  hCV9581635	rs1748195	hCV1778963	rs1058897	0.51	0.9	0.958
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  hCV9581635	rs1748195	hCV1918041	rs4587594	0.51	0.9	0.979
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  hCV9581635	rs1748195	hCV25971202	rs10889335	0.51	0.9	0.9376
  hCV9581635	rs1748195	hCV26412183	rs1748199	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV26412184	rs11207990	0.51	0.9	1
  hCV9581635	rs1748195	hCV27320451	rs4350231	0.51	0.9	0.958
  hCV9581635	rs1748195	hCV27320465	rs641540	0.51	0.9	1
  hCV9581635	rs1748195	hCV29103721	rs6678483	0.51	0.9	1
  hCV9581635	rs1748195	hCV29103722	rs6675401	0.51	0.9	1
  hCV9581635	rs1748195	hCV29103723	rs4329540	0.51	0.9	1
  hCV9581635	rs1748195	hCV29647381	rs6690733	0.51	0.9	0.9791
  hCV9581635	rs1748195	hCV29749081	rs10493322	0.51	0.9	0.959
  hCV9581635	rs1748195	hCV30224093	rs7539035	0.51	0.9	1
  hCV9581635	rs1748195	hCV31145250	rs10889353	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV31145255	rs11208000	0.51	0.9	0.9777
  hCV9581635	rs1748195	hCV31145262	rs10889352	0.51	0.9	0.9539
  hCV9581635	rs1748195	hCV31145264	rs10789119	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV31145266	rs10789118	0.51	0.9	0.959
  hCV9581635	rs1748195	hCV31145267	rs11485618	0.51	0.9	0.9576
  hCV9581635	rs1748195	hCV31145269	rs6587980	0.51	0.9	1
  hCV9581635	rs1748195	hCV31145277	rs10889350	0.51	0.9	1
  hCV9581635	rs1748195	hCV31145279	rs10889349	0.51	0.9	1
  hCV9581635	rs1748195	hCV31145282	rs11207997	0.51	0.9	0.9373
  hCV9581635	rs1748195	hCV31145290	rs12042319	0.51	0.9	0.959
  hCV9581635	rs1748195	hCV31145291	rs11207995	0.51	0.9	0.9578
  hCV9581635	rs1748195	hCV31145298	rs11207992	0.51	0.9	0.959
  hCV9581635	rs1748195	hCV31145302	rs12116574	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV31145332	rs11207981	0.51	0.9	1
  hCV9581635	rs1748195	hCV3122390	rs1748200	0.51	0.9	1
  hCV9581635	rs1748195	hCV316299	rs1168026	0.51	0.9	1
  hCV9581635	rs1748195	hCV316303	rs1168031	0.51	0.9	1
  hCV9581635	rs1748195	hCV32220452	rs12090886	0.51	0.9	1
  hCV9581635	rs1748195	hCV32220453	rs10889337	0.51	0.9	0.9791
  hCV9581635	rs1748195	hCV32220467	rs10889333	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV32220469	rs10889332	0.51	0.9	1
  hCV9581635	rs1748195	hCV32220470	rs11207974	0.51	0.9	1
  hCV9581635	rs1748195	hCV32220491	rs11577840	0.51	0.9	1
  hCV9581635	rs1748195	hCV32220495	rs11207969	0.51	0.9	1
  hCV9581635	rs1748195	hCV408090	rs1183260	0.51	0.9	1
  hCV9581635	rs1748195	hCV445207	rs1627591	0.51	0.9	1
  hCV9581635	rs1748195	hCV71419	rs2131925	0.51	0.9	1
  hCV9581635	rs1748195	hCV857102	rs624660	0.51	0.9	1
  hCV9581635	rs1748195	hCV857103	rs636497	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV857104	rs636523	0.51	0.9	0.959
  hCV9581635	rs1748195	hCV857108	rs597078	0.51	0.9	1
  hCV9581635	rs1748195	hCV857109	rs597470	0.51	0.9	1
  hCV9581635	rs1748195	hCV857110	rs583609	0.51	0.9	1
  hCV9581635	rs1748195	hCV857121	rs642845	0.51	0.9	1
  hCV9581635	rs1748195	hCV857122	rs656297	0.51	0.9	1
  hCV9581635	rs1748195	hCV857123	rs638305	0.51	0.9	1
  hCV9581635	rs1748195	hCV857127	rs631106	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV9508668	rs1781195	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581062	rs998403	0.51	0.9	0.958
  hCV9581635	rs1748195	hCV9581551	rs1168040	0.51	0.9	0.9151
  hCV9581635	rs1748195	hCV9581570	rs1168036	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581571	rs1002687	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581580	rs1168032	0.51	0.9	0.9789
  hCV9581635	rs1748195	hCV9581581	rs1168030	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581590	rs1168018	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581606	rs1168022	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581615	rs1748201	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581636	rs3850634	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV9581680	rs1748197	0.51	0.9	1
  hCV9581635	rs1748195	hCV9581691	rs1570694	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV9583244	rs783291	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588770	rs1007205	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588793	rs1168009	0.51	0.9	0.9575
  hCV9581635	rs1748195	hCV9588794	rs1168010	0.51	0.9	0.9572
  hCV9581635	rs1748195	hCV9588829	rs1781212	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588850	rs1168013	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588862	rs995000	0.51	0.9	0.979
  hCV9581635	rs1748195	hCV9588875	rs1168086	0.51	0.9	0.9551
  hCV9581635	rs1748195	hCV9588886	rs1168089	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588930	rs1168099	0.51	0.9	1
  hCV9581635	rs1748195	hCV9588985	rs1168124	0.51	0.9	1
  hCV9581635	rs1748195	hDV75176134	rs1781221	0.51	0.9	1
  hCV9588862	rs995000	hCV11864156	rs10889334	0.51	0.9	1
  hCV9588862	rs995000	hCV11864162	rs1167998	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV11865171	rs11208004	0.51	0.9	1
  hCV9588862	rs995000	hCV11865185	rs10789117	0.51	0.9	0.979
  hCV9588862	rs995000	hCV11865201	rs10159255	0.51	0.9	0.979
  hCV9588862	rs995000	hCV12103105	rs1184865	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV12103127	rs1979722	0.51	0.9	0.9789
  hCV9588862	rs995000	hCV12103499	rs2029763	0.51	0.9	1
  hCV9588862	rs995000	hCV12103502	rs1168023	0.51	0.9	0.958
  hCV9588862	rs995000	hCV1236535	rs1168042	0.51	0.9	0.959
  hCV9588862	rs995000	hCV149783	rs1168045	0.51	0.9	0.979
  hCV9588862	rs995000	hCV16214290	rs2366638	0.51	0.9	0.959
  hCV9588862	rs995000	hCV1778957	rs3913007	0.51	0.9	1
  hCV9588862	rs995000	hCV1778958	rs634341	0.51	0.9	0.9558
  hCV9588862	rs995000	hCV1778963	rs10158897	0.51	0.9	0.979
  hCV9588862	rs995000	hCV1778964	rs659656	0.51	0.9	1
  hCV9588862	rs995000	hCV1778965	rs637723	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV1918028	rs10157265	0.51	0.9	0.958
  hCV9588862	rs995000	hCV1918041	rs4587594	0.51	0.9	1
  hCV9588862	rs995000	hCV1918054	rs10889347	0.51	0.9	0.979
  hCV9588862	rs995000	hCV2015148	rs11208007	0.51	0.9	0.9032
  hCV9588862	rs995000	hCV25971202	rs10889335	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV26412183	rs1748199	0.51	0.9	0.9577
  hCV9588862	rs995000	hCV26412184	rs11207990	0.51	0.9	0.9521
  hCV9588862	rs995000	hCV27320451	rs4350231	0.51	0.9	0.979
  hCV9588862	rs995000	hCV27320465	rs641540	0.51	0.9	0.9586
  hCV9588862	rs995000	hCV29103721	rs6678483	0.51	0.9	0.979
  hCV9588862	rs995000	hCV29103722	rs6675401	0.51	0.9	0.979
  hCV9588862	rs995000	hCV29103723	rs4329540	0.51	0.9	0.979
  hCV9588862	rs995000	hCV29647381	rs6690733	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV29749081	rs10493322	0.51	0.9	1
  hCV9588862	rs995000	hCV30224093	rs7539035	0.51	0.9	0.979
  hCV9588862	rs995000	hCV31145250	rs10889353	0.51	0.9	1
  hCV9588862	rs995000	hCV31145255	rs11208000	0.51	0.9	0.9551
  hCV9588862	rs995000	hCV31145262	rs10889352	0.51	0.9	1
  hCV9588862	rs995000	hCV31145264	rs10789119	0.51	0.9	1
  hCV9588862	rs995000	hCV31145266	rs10789118	0.51	0.9	1
  hCV9588862	rs995000	hCV31145267	rs11485618	0.51	0.9	1
  hCV9588862	rs995000	hCV31145269	rs6587980	0.51	0.9	0.979
  hCV9588862	rs995000	hCV31145277	rs10889350	0.51	0.9	0.959
  hCV9588862	rs995000	hCV31145279	rs10889349	0.51	0.9	0.959
  hCV9588862	rs995000	hCV31145282	rs11207997	0.51	0.9	0.9169
  hCV9588862	rs995000	hCV31145290	rs12042319	0.51	0.9	1
  hCV9588862	rs995000	hCV31145291	rs11207995	0.51	0.9	0.9789
  hCV9588862	rs995000	hCV31145298	rs11207992	0.51	0.9	1
  hCV9588862	rs995000	hCV31145302	rs12116574	0.51	0.9	1
  hCV9588862	rs995000	hCV31145332	rs11207981	0.51	0.9	0.9538
  hCV9588862	rs995000	hCV3122390	rs1748200	0.51	0.9	0.959
  hCV9588862	rs995000	hCV316299	rs1168026	0.51	0.9	0.959
  hCV9588862	rs995000	hCV316303	rs1168031	0.51	0.9	0.9586
  hCV9588862	rs995000	hCV32220452	rs12090886	0.51	0.9	1
  hCV9588862	rs995000	hCV32220453	rs10889337	0.51	0.9	0.9585
  hCV9588862	rs995000	hCV32220467	rs10889333	0.51	0.9	1
  hCV9588862	rs995000	hCV32220469	rs10889332	0.51	0.9	0.979
  hCV9588862	rs995000	hCV32220470	rs11207974	0.51	0.9	0.959
  hCV9588862	rs995000	hCV32220491	rs11577840	0.51	0.9	0.9586
  hCV9588862	rs995000	hCV32220495	rs11207969	0.51	0.9	0.979
  hCV9588862	rs995000	hCV408090	rs1183260	0.51	0.9	0.9566
  hCV9588862	rs995000	hCV445207	rs1627591	0.51	0.9	0.959
  hCV9588862	rs995000	hCV71419	rs2131925	0.51	0.9	0.959
  hCV9588862	rs995000	hCV857102	rs624660	0.51	0.9	0.979
  hCV9588862	rs995000	hCV857103	rs636497	0.51	0.9	0.9577
  hCV9588862	rs995000	hCV857104	rs636523	0.51	0.9	1
  hCV9588862	rs995000	hCV857108	rs597078	0.51	0.9	0.958
  hCV9588862	rs995000	hCV857109	rs597470	0.51	0.9	0.959
  hCV9588862	rs995000	hCV857110	rs583609	0.51	0.9	0.979
  hCV9588862	rs995000	hCV857121	rs642845	0.51	0.9	0.958
  hCV9588862	rs995000	hCV857122	rs656297	0.51	0.9	0.979
  hCV9588862	rs995000	hCV857123	rs638305	0.51	0.9	0.959
  hCV9588862	rs995000	hCV857127	rs631106	0.51	0.9	0.9577
  hCV9588862	rs995000	hCV9508668	rs1781195	0.51	0.9	0.979
  hCV9588862	rs995000	hCV9581062	rs998403	0.51	0.9	1
  hCV9588862	rs995000	hCV9581570	rs1168036	0.51	0.9	1
  hCV9588862	rs995000	hCV9581571	rs1002687	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9581580	rs1168032	0.51	0.9	0.958
  hCV9588862	rs995000	hCV9581581	rs1168030	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9581590	rs1168018	0.51	0.9	0.9789
  hCV9588862	rs995000	hCV9581606	rs1168022	0.51	0.9	0.9558
  hCV9588862	rs995000	hCV9581615	rs1748201	0.51	0.9	0.9789
  hCV9588862	rs995000	hCV9581635	rs1748195	0.51	0.9	0.979
  hCV9588862	rs995000	hCV9581636	rs3850634	0.51	0.9	1
  hCV9588862	rs995000	hCV9581680	rs1748197	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9581691	rs1570694	0.51	0.9	1
  hCV9588862	rs995000	hCV9583244	rs783291	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9588770	rs1007205	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9588793	rs1168009	0.51	0.9	0.9365
  hCV9588862	rs995000	hCV9588794	rs1168010	0.51	0.9	0.936
  hCV9588862	rs995000	hCV9588829	rs1781212	0.51	0.9	0.959
  hCV9588862	rs995000	hCV9588850	rs1168013	0.51	0.9	0.979
  hCV9588862	rs995000	hCV9588875	rs1168086	0.51	0.9	0.9551
  hCV9588862	rs995000	hCV9588886	rs1168089	0.51	0.9	0.979
  hCV9588862	rs995000	hCV9588930	rs1168099	0.51	0.9	0.979
  hCV9588862	rs995000	hCV9588985	rs1168124	0.51	0.9	0.959
  hCV9588862	rs995000	hDV75176134	rs1781221	0.51	0.9	0.959
  hCV9596963	rs6115	hCV9596972	rs6112	0.51	0.9	0.9634
  hCV9604851	rs1805002	hDV77041261	rs4758402	0.51	0.9	1
  hDV70661573	rs16875009	hCV2928259	rs6867948	0.51	0.409905558	0.656
  hDV70661573	rs16875009	hCV2928266	rs11742566	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928267	rs12517136	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928268	rs11134096	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928269	rs11134097	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928270	rs12515050	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928271	rs12520783	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928278	rs12522919	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928283	rs12518805	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928284	rs12518833	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928288	rs11748003	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928289	rs7446660	0.51	0.409905558	0.4246
  hDV70661573	rs16875009	hCV2928293	rs12517784	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV2928295	rs1428025	0.51	0.409905558	0.4246
  hDV70661573	rs16875009	hCV2928306	rs1428024	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV32226945	rs12521996	0.51	0.409905558	1
  hDV70661573	rs16875009	hCV32226946	rs12517751	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703783	rs16874942	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703799	rs16874970	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703820	rs16874994	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703822	rs16874998	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703832	rs16875012	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703845	rs16875031	0.51	0.409905558	0.8803
  hDV70661573	rs16875009	hDV70703846	rs16875033	0.51	0.409905558	1
  hDV70661573	rs16875009	hDV70703851	rs16875038	0.51	0.409905558	1
  hDV70938014	rs17321515	hCV11593303	rs2980871	0.51	0.9	0.9634
  hDV70938014	rs17321515	hCV12004940	rs2001844	0.51	0.9	1
  hDV70938014	rs17321515	hCV15883779	rs2980869	0.51	0.9	1
  hDV70938014	rs17321515	hCV15883790	rs2980875	0.51	0.9	0.9619
  hDV70938014	rs17321515	hCV15954624	rs2954022	0.51	0.9	0.9634
  hDV70938014	rs17321515	hCV15954645	rs2954029	0.51	0.9	0.9634
  hDV70938014	rs17321515	hCV26372062	rs2980856	0.51	0.9	1
  hDV70938014	rs17321515	hCV26372064	rs2980855	0.51	0.9	1
  hDV70938014	rs17321515	hCV26372065	rs2980854	0.51	0.9	1
  hDV70938014	rs17321515	hCV26372066	rs2980853	0.51	0.9	1
  hDV70938014	rs17321515	hCV26372069	rs2980882	0.51	0.9	1
  hDV70938014	rs17321515	hCV29719123	rs6982636	0.51	0.9	1
  hDV70938014	rs17321515	hCV309481	rs2954019	0.51	0.9	1
  hDV70938014	rs17321515	hCV469160	rs2954031	0.51	0.9	0.9279
  hDV70938014	rs17321515	hCV85515	rs10808546	0.51	0.9	0.9064
  hDV70973697	rs17593921	hDV70715540	rs16891266	0.51	0.612665933	0.6234
  hDV70977122	rs17616652	hCV11627552	rs2316667	0.51	0.442542981	0.7059
  hDV70977122	rs17616652	hCV1718966	rs4968305	0.51	0.442542981	0.7074
  hDV70977122	rs17616652	hCV26683367	rs9894300	0.51	0.442542981	0.6395
  hDV70977122	rs17616652	hCV26583368	rs2004580	0.51	0.442542981	0.6405
  hDV70977122	rs17616652	hCV29195269	rs7221042	0.51	0.442542981	0.7843
  hDV70977122	rs17616652	hCV30515746	rs10491149	0.51	0.442542981	0.7843
  hDV70977122	rs17616652	hCV31479223	rs11570460	0.51	0.442542981	0.7356
  hDV70977122	rs17616652	hCV31479380	rs4520895	0.51	0.442542981	0.642
  hDV70977122	rs17616652	hCV7451110	rs1515754	0.51	0.442542981	0.7356
  hDV70977122	rs17616652	hCV9268649	rs16941168	0.51	0.442542981	0.5852
  hDV70977122	rs17616652	hDV70590478	rs9897338	0.51	0.442542981	0.642
  hDV70977122	rs17616652	hDV70751669	rs16941353	0.51	0.442542981	0.7843
  hDV70977122	rs17616652	hDV70751822	rs16941584	0.51	0.442542981	0.7366
  hDV70977122	rs17616652	hDV70975179	rs17603901	0.51	0.442542981	0.6562
  hDV70977122	rs17616652	hDV70987720	rs17676978	0.51	0.442542981	0.7843
  hDV70977122	rs17616652	hDV75285090	rs2667804	0.51	0.442542981	0.7074

• TABLE 7
  Association test results from two MI case-control studies

  CCF

  UCSF

  SNP	Gene Symbol	Risk Allele	OR (95% CI)	P	Strata	Model	OR (95% CI)	P	Strata	Model	Tested*

  rs6668968	AQP10	A	1.29	(1.07-1.57)	0.008	ALL	add	1.16	(1.00-1.35)	0.050	ALL	add	†
  rs13078881	BTD	G	2.95	(1.27-6.89)	0.012	F	add	1.73	(0.94-3.20)	0.079	F	add	†
  rs1051038	COG2	A	1.23	(0.99-1.53)	0.063	ALL	add	1.19	(0.97-1.46)	0.088	ALL	rec	†
  rs2035029	DCC	G	1.35	(1.04-1.76)	0.024	ALL	dom	1.22	(1.00-1.50)	0.053	ALL	dom	†
  Chr17:
  74022684	DNAHL1	C	1.85	(0.95-3.63)	0.072	ALL	add	1.96	(0.97-3.94)	0.060	M	add	†
  rs34639489	ERV3	C	1.16	(0.98-1.38)	0.092	ALL	add	1.13	(0.98-1.30)	0.086	ALL	add	†
  rs4149965	EXO1	A	1.34	(1.03-1.73)	0.028	M	add	1.38	(1.10-1.73)	0.005	M	add	†
  rs2304024	FAT2	G	1.20	(0.97-1.50)	0.097	ALL	add	1.23	(1.04-1.46)	0.019	ALL	add	†
  	GALNAC4S-
  rs12915	6ST	C	1.17	(0.98-1.40)	0.080	ALL	add	1.13	(0.98-1.30)	0.088	ALL	add	†
  rs197922	GOSR2	A	1.29	(0.98-1.70)	0.071	F	add	1.17	(1.01-1.34)	0.032	ALL	add	†
  rs2296434	HPS1	G	1.39	(1.01-1.90)	0.042	ALL	add	1.34	(0.96-1.85)	0.082	M	add	†
  rs1060446	HPSE2	C	1.27	(1.07-1.50)	0.006	ALL	add	1.14	(1.00-1.31)	0.052	ALL	add	†
  rs3739998	KIAA1462	G	1.26	(0.96-1.65)	0.093	F	add	1.30	(1.06-1.61)	0.012	F	add	†
  rs3110234	LIFR	T	1.19	(0.96-1.46)	0.066	ALL	gen	1.17	(0.99-1.39)	0.070	ALL	gen	†
  rs28756981	MLH3	T	3.23	(1.10-9.50)	0.033	M	add	4.58	(1.28-16.33)	0.019	M	add	†
  rs11051410	none	G	1.22	(1.01-1.46)	0.038	ALL	add	1.16	(1.00-1.34)	0.045	ALL	add	†
  rs1023899	none	A	1.82	(1.19-2.78)	0.006	M	add	1.40	(0.99-1.97)	0.059	M	add	†
  rs2959189	none	G	1.59	(1.10-2.30)	0.014	ALL	dom	1.27	(0.97-1.67)	0.085	ALL	dom	†
  rs10622	none	T	1.27	(0.98-1.65)	0.066	ALL	rec	1.28	(1.04-1.57)	0.018	ALL	rec	†
  rs7736962	none	A	1.30	(1.01-1.67)	0.044	ALL	rec	1.30	(0.98-1.72)	0.064	M	rec	†
  rs4706769	none	T	1.17	(0.99-1.39)	0.067	ALL	add	1.26	(1.04-1.53)	0.017	M	add	†
  rs3196714	ODAM	T	1.45	(0.95-2.23)	0.085	ALL	dom	1.32	(0.95-1.82)	0.095	ALL	dom	†
  rs1151640	OR13G1	C	1.34	(1.12-1.60)	0.001	ALL	add	1.16	(1.01-1.33)	0.042	ALL	add	†
  rs11219508	OR8G2	C	1.45	(0.98-2.15)	0.065	F	dom	1.34	(1.01-1.78)	0.042	F	dom	†
  rs2278586	OXER1	C	1.37	(0.98-1.91)	0.063	F	add	1.35	(1.06-1.72)	0.014	F	add	†
  rs2970871	PPARGC1A	C	1.17	(0.98-1.40)	0.080	ALL	add	1.26	(0.98-1.61)	0.072	ALL	dom	†
  rs3750533	PRPF4	T	1.21	(0.97-1.52)	0.099	M	add	1.20	(0.98-1.47)	0.076	M	add	†
  rs2297322	SLC15A1	C	1.44	(1.02-2.04)	0.037	M	add	1.32	(0.98-1.76)	0.066	M	add	†
  rs2072549	SLC7A4	A	1.24	(1.00-1.53)	0.046	ALL	add	1.17	(0.98-1.39)	0.079	ALL	add	†
  rs1785934	STATIP1	C	1.36	(0.98-1.88)	0.067	M	dom	1.25	(1.02-1.53)	0.029	ALL	dom	†
  rs11735477	TKTL2	A	1.35	(1.04-1.75)	0.026	ALL	dom	1.28	(0.95-1.72)	0.098	M	dom	†
  rs1042589	TPO	C	1.24	(0.99-1.56)	0.061	M	add	1.19	(1.04-1.36)	0.011	ALL	add	†
  rs1108225	TRPM3	A	1.23	(1.00-1.50)	0.048	ALL	add	1.23	(1.05-1.45)	0.012	ALL	add	†
  rs10083789	USP31	A	1.22	(1.01-1.46)	0.036	ALL	add	1.20	(1.04-1.39)	0.012	ALL	add	†
  rs35305327	WDR31	A	3.64	(1.04-12.75)	0.043	ALL	add	2.48	(1.13-5.46)	0.023	ALL	add	†
  rs1465789	ZNF132	G	1.21	(0.98-1.50)	0.080	M	add	1.19	(0.99-1.43)	0.071	M	add	†
  rs2017252	ZNF273	A	1.17	(0.99-1.39)	0.066	ALL	add	1.18	(1.03-1.35)	0.017	ALL	add	†
  rs2884554	ZNF714	G	1.25	(0.97-1.61)	0.079	ALL	add	1.19	(0.99-1.44)	0.063	ALL	add	†
  rs3027309	ALOX12B	T	1.27	(1.02-1.59)	0.035	ALL	add	1.18	(0.99-1.41)	0.068	ALL	add	‡
  rs2296436	HPS1	T	1.36	(0.99-1.85)	0.054	ALL	add	1.32	(0.95-1.82)	0.095	M	add	‡
  rs1042636	CASR	G	1.64	(0.94-2.86)	0.082	F	add	1.30	(1.00-1.70)	0.047	ALL	add	‡
  rs1376251	TAS2R50	C	1.26	(1.05-1.52)	0.014	ALL	add	1.23	(1.07-1.41)	0.004	ALL	add	‡
  rs12102203	RC3	G	1.38	(1.15-1.64)	<0.001	ALL	add	1.18	(1.03-1.35)	0.014	ALL	add	‡
  rs2286394	WDR55	T	1.24	(1.01-1.53)	0.037	ALL	add	1.18	(1.00-1.39)	0.044	ALL	add	‡
  rs2307469	EIF2AK2	C	1.48	(0.95-2.32)	0.086	ALL	add	1.71	(1.17-2.51)	0.006	ALL	add	‡
  rs3213646	MGC16943	C	1.22	(0.97-1.53)	0.092	M	add	1.18	(0.98-1.43)	0.076	M	add	‡
  rs5985	F13A1	A	1.23	(1.01-1.51)	0.040	ALL	add	1.21	(1.04-1.41)	0.013	ALL	add	‡
  Chr2:
  37081301	KIAA1414	G	1.54	(1.07-2.20)	0.019	ALL	add	1.59	(1.19-2.12)	0.002	ALL	add	‡§
  rs1042164	IER2	T	1.31	(1.03-1.69)	0.028	ALL	add	1.22	(0.98-1.52)	0.070	ALL	add	‡
  rs6761276	IL1F10	T	1.25	(1.03-1.50)	0.020	ALL	add	1.23	(1.07-1.41)	0.004	ALL	add	‡
  rs6743376	IL1F10	C	1.24	(1.03-1.49)	0.024	ALL	add	1.22	(1.06-1.40)	0.006	ALL	add	‡
  rs943133	LOC391102	A	1.24	(1.02-1.51)	0.030	ALL	add	1.19	(1.02-1.38)	0.023	ALL	add	‡
  rs3130210	LOC442203	T	1.24	(1.01-1.53)	0.037	ALL	add	1.29	(1.09-1.52)	0.002	ALL	add	‡
  rs3129196	LOC442203	A	1.25	(1.02-1.53)	0.035	ALL	add	1.29	(1.10-1.52)	0.002	ALL	add	‡
  rs12510359	PALLD	G	1.26	(1.05-1.51)	0.011	ALL	add	1.22	(1.07-1.41)	0.004	ALL	add	‡
  rs7439293	PALLD	A	1.21	(1.01-1.46)	0.042	ALL	add	1.22	(1.06-1.40)	0.006	ALL	add
  rs3798220	LPA	C	4.71	(0.00-0.00)	<0.001	ALL	add	1.76	(0.00-0.00)	0.014	ALL	add	‡
  rs10082504	MKI67	C	1.38	(1.03-1.84)	0.034	ALL	add	1.26	(1.01-1.59)	0.043	ALL	add	‡
  rs4750685	MKI67	G	1.33	(0.98-1.81)	0.069	ALL	add	1.26	(1.00-1.59)	0.054	ALL	add	‡¶
  rs3900940	MYH15	C	0.32	(0.97-1.78)	0.078	F	add	1.31	(1.05-1.63)	0.015	F	add	‡∥
  rs12145360	MYOM3	A	1.36	(0.98-1.90)	0.069	M	add	1.59	(1.22-2.07)	0.001	M	add	‡
  rs12684749	NFIB	A	2.59	(1.39-4.82)	0.003	ALL	add	1.36	(0.95-1.96)	0.097	ALL	add	‡
  rs3808117	GRM8	T	1.58	(1.26-1.98)	0.000	ALL	add	1.21	(1.02-1.44)	0.026	ALL	add	‡
  rs2277838	P2RXL1	A	1.27	(1.02-1.58)	0.032	ALL	add	1.21	(1.02-1.44)	0.032	ALL	add	‡
  rs3813135	PGLYRP2	C	1.25	(0.96-1.63)	0.095	ALL	dom	1.27	(1.04-1.55)	0.020	ALL	dom	‡
  rs211070	PRKG1	G	1.71	(1.06-2.76)	0.029	ALL	add	1.42	(1.03-1.97)	0.034	ALL	add	‡
  rs619203	ROS1	C	1.31	(1.06-1.61)	0.012	ALL	add	1.30	(1.11-1.52)	0.001	ALL	add	‡
  rs529038	ROS1	T	1.31	(1.07-1.61)	0.010	ALL	add	1.31	(1.12-1.53)	0.001	ALL	add	‡
  rs117090921	SERPINA9	A	2.31	(1.14-4.66)	0.019	F	rec	1.50	(0.94-2.38)	0.087	F	rec	‡
  rs11628722	SERPINA9	G	1.26	(0.99-1.60)	0.058	ALL	add	1.17	(0.98-1.39)	0.091	ALL	add	‡
  rs4747647	TAF3	A	1.22	(1.02-1.47)	0.033	ALL	add	1.15	(1.00-1.32)	0.056	ALL	add	‡
  rs1010	VAMP8	C	1.36	(1.13-1.64)	0.001	ALL	add	1.25	(1.09-1.43)	0.002	ALL	add	‡∥
  rs6685323	AQP10	T	1.33	(1.110-1.61)	0.003	ALL	add	1.19	(1.03-1.38)	0.020	ALL	add	#
  rs6480771	DUSP13	G	1.20	(1.01-1.43)	0.084	ALL	gen	1.07	(0.93-1.23)	0.063	ALL	gen	#
  rs887	FLJ42562	G	1.21	(1.01-1.46)	0.040	ALL	add	1.17	(1.01-1.35)	0.032	ALL	add	#
  rs28711149	OR13G1	T	1.21	(1.01-1.45)	0.038	ALL	add	1.29	(0.97-1.72)	0.083	ALL	dom	#
  rs1126799	TPO	C	1.16	(0.98-1.37)	0.091	ALL	add	1.22	(0.99-1.51)	0.064	ALL	rec	#
  SNP, single nucleotide polymorphism; CCF, Cleveland Clinic Foundation; USCF, University of California, San Francisco; OR, odds ratio; CI, confidence interval;
  *This column indicates the location of published results for the testing of the association for each SNP and incident coronary heart disease in the Atherosclerosis Risk in Communities cohort.
  †Online supplemental table II, Meyer et al., “A GOSR2 variant is associated with hypertension”, Hypertension, 2008;
  ‡Morrison et al.33;
  §previously reported as Chr2:37139448 in build 35;
  ∥Bare et al.34;
  ¶previously reported as Chr10: 129793007 in build 35;
  #not reported because good multiplex assays could not be made

• TABLE 8
  Descriptive information by race and GOSR2 genotype

  Whites (N = 9,861)

  Blacks (N = 3,528)

  	ArgArg	LysArg	LysLys		ArgArg	LysArg	LysLys
  	(n = 4,264)	(n = 4,398)	(n = l,199)	P*	(n = l,698)	(n = l,494)	(n = 336)	P*

  Mean ± SD

  Age, y	54 ± 5.7	54 ± 5.7	54 ± 5.8	0.26	53 ± 5.7	53 ± 5.9	54 ± 5.8	0.01
  SBP (mm Hg)†	115.5 ± 15.6	116.7 ± 16.1	116.6 ± 16.0	<0.01	125.4 ± 19.6	125.5 ± 20.4	128.5 ± 21.2	0.15
  DBP (mm Hg)†	70.5 ± 9.6	70.9 ± 9.8	71.0 ± 9.9	0.09	78.5 ± 11.3	78.1 ± 12.0	79.2 ± 12.3	0.96
  Waist circumference (cm)	95.5 ± 13.4	96.4 ± 13.5	95.8 ± 13.2	0.05	99.0 ± 15.5	98.8 ± 14.8	99.2 ± 14.6	0.88
  Ln(triglycerides) (mmol/L)‡	0.27 ± 0.50	0.29 ± 0.51	0.28 ± 0.53	0.15	0.09 ± 0.46	0.09 ± 0.48	0.10 ± 0.45	0.80
  HDL cholesterol (mmol/L)	1.3 ± 0.4	1.3 ± 0.4	1.3 ± 0.4	0.96	1.4 ± 0.4	1.4 ± 0.5	1.4 ± 0.5	0.13
  Glucose (mmol/L)§	5.5 ± 0.5	5.5 ± 0.5	5.5 ± 0.5	0.93	5.5 ± 0.6	5.5 ± 0.5	5.4 ± 0.6	0.15
  CA IMT (mm)	0.73 ± 0.18	0.74 ± 0.18	0.74 ± 0.17	0.02	0.74 ± 0.16	0.73 ± 0.16	0.75 ± 0.17	0.60

  No. (%)

  Male	1,952 (46)	1,983 (45)	551 (46)	0.77	643 (38)	542 (36)	116 (35)	0.42
  Hypertension	1,012 (24)	1,181 (27)	314 (26)	<0.01	926 (55)	797 (53)	186 (56)	0.66
  Diabetes	327 (8)	375 (9)	105 (9)	0.26	308 (19)	261 (18)	65 (20)	0.68
  SD, standard deviation; CA, carotid artery; IMT, intima media thickness;
  *P values are for the differences between genotypes (F-test for continuous variables or X2 test for categorical variables);
  †Excluding participants taking anti-hypertensive medications;
  ‡among those who fasted for at least 8 hours;
  §samong nondiabetics who fasted for at least 8 hours

• TABLE 9
  OR and 95% CI for the association between GOSR2 (Lys67Arg, rs197922), hypertension,
  and carotid artery thickness

  Whites (N = 9,822)

  Blacks (N = 3,513)

  	n	OR (95% CI)*	P‡	n	OR (95% CI)*	P‡

  Hypertension	2,506	1.09 (1.02 to 1.17)	0.01	1,909	0.96 (0.87 to 1.07)	0.47
  Elevated SBP (≥75% tile)	2,531	1.08 (1.00 to 1.15)†	0.04	909	1.04 (0.92 to 1.17)†	0.52
  Elevated DBP (≥75% tile)	2,606	1.08 (1.01 to 1.16)†	0.02	904	1.03 (0.92 to 1.16)†	0.57
  Thick CA IMT§ (≥75% tile)	2,284	1.09 (1.01 to 1.17)	0.02	830	0.99 (0.88 to 1.13)	0.92
  OR, odds ratio;
  CI, confidence interval;
  n, number of affected;
  SBP, systolic blood pressure;
  DBP, diastolic blood pressure;
  CA, carotid artery;
  IMT, intima media thickness;
  *adjusted for gender and age at baseline;
  †additionally adjusted for anti-hypertensive medication use;
  ‡P is Wald test p-value;
  §N = 9,302 whites and 3,146 blacks

• TABLE 10
  UCSF1

  							Case
  					Case	Control	Allele
  marker	rs	Gene	RiskAllele	NonRiskAllele	Samples**	Samples**	Freq*
  hCV11623551	rs8073829	LOC731128	C	T	754	971	0.88
  hCV15885004	rs2277614	LRRC37A2	A	G	753	970	0.04
  hCV2275263	rs197912	LRRC37A2	A	T	754	972	0.38
  hCV2275272	rs197920	GOSR2	T	C	721	861	0.32
  hCV2275276	rs197925	GOSR2	A	G	716	862	0.41
  hCV2592654	rs1662577	LRRC37A2	A	C	753	970	0.40
  hCV2592662	rs2191033	GOSR2	G	A	715	859	0.41
  hCV2592715	rs3851792	LRRC37A2	A	T	715	859	0.57
  hCV2592759	rs8080126	LRRC37A2	A	C	754	973	0.73
  hCV26660340	rs4968246	LRRC37A2	G	C	754	973	0.40
  hCV26683367	rs9894300	LOC731128	G	C	754	973	0.88
  hCV26683368	rs2004580	LOC731128	C	T	755	973	0.88
  hCV29195255	rs8068715	LRRC37A2	C	A	723	858	0.57
  hCV29195260	rs3851798	LRRC37A2	A	G	725	863	0.57
  hCV2960489	rs3785889	GOSR2	G	A	719	861	0.51
  hCV31466171	rs10853085	LRRC37A2	G	A	718	863	0.40
  hCV341736	rs11653589	LRRC37A2	T	C	724	860	0.58
  hCV537525	rs197943	LRRC37A2	C	A	754	971	0.06
  hCV7451269	rs1662594	LRRC37A2	A	G	725	861	0.39
  hCV7480314	rs3851799	LRRC37A2	C	T	724	862	0.58
  hDV70751699	rs16941393	LRRC37A2	A	T	755	973	0.92
  hDV70751704	rs16941401	LRRC37A2	T	A	752	972	0.92
  hDV70751706	rs16941404	LRRC37A2	G	C	754	968	0.20
  hDV70977122	rs17616652	LRRC37A2	A	G	752	973	0.92

  	Control							r{circumflex over ( )}2 with
  	Allele							hCV2275273
  marker	Freq*	OR*	OR95L*	OR95U*	P_value	Strata	Model	(GOSR2)
  hCV11623551	0.85	1.28	1.05	1.56	0.014	AllvsAll	add	0.043
  hCV15885004	0.03	1.47	1.02	2.13	0.041	AllvsAll	add	0.061
  hCV2275263	0.35	1.17	1.02	1.35	0.026	AllvsAll	add	0.851
  hCV2275272	0.29	1.15	0.99	1.33	0.076	AllvsAll	add	0.82
  hCV2275276	0.38	1.15	1.00	1.33	0.057	AllvsAll	add	0.737
  hCV2592654	0.37	1.13	0.99	1.30	0.076	AllvsAll	add	0.806
  hCV2592662	0.38	1.16	1.01	1.34	0.041	AllvsAll	add	0.739
  hCV2592715	0.54	1.14	0.98	1.31	0.085	AllvsAll	add	0.252
  hCV2592759	0.71	1.14	0.98	1.32	0.095	AllvsAll	add	0.015
  hCV26660340	0.36	1.15	1.00	1.32	0.045	AllvsAll	add	0.541
  hCV26683367	0.85	1.28	1.05	1.56	0.014	AllvsAll	add	0.043
  hCV26683368	0.85	1.26	1.04	1.54	0.019	AllvsAll	add	0.044
  hCV29195255	0.54	1.14	0.99	1.32	0.066	AllvsAll	add	0.254
  hCV29195260	0.54	1.15	1.00	1.33	0.056	AllvsAll	add	0.254
  hCV2960489	0.47	1.16	1.00	1.33	0.044	AllvsAll	add	0.512
  hCV31466171	0.37	1.15	0.99	1.32	0.062	AllvsAll	add	0.79
  hCV341736	0.54	1.16	1.00	1.34	0.046	AllvsAll	add	0.25
  hCV537525	0.04	1.45	1.07	1.97	0.016	AllvsAll	add	0.028
  hCV7451269	0.36	1.13	0.98	1.31	0.088	AllvsAll	add	0.796
  hCV7480314	0.54	1.14	0.99	1.32	0.068	AllvsAll	add	0.253
  hDV70751699	0.90	1.22	0.96	1.55	0.098	AllvsAll	add	0
  hDV70751704	0.90	1.23	0.97	1.56	0.089	AllvsAll	add	0
  hDV70751706	0.18	1.17	0.99	1.39	0.068	AllvsAll	add	0.453
  hDV70977122	0.89	1.46	1.16	1.84	0.001	AllvsAll	add	0.042
  notes:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  Study design in UCSF1: MI cases vs No CHD controls

• TABLE 11
  Risk factors for MI in participants of three case-control studies

  Study 1

  Study 2

  Study 3

  	Cases	Controls	Cases	Controls	Cases	Controls
  	(n = 762)	(n = 857)	(n = 579)	(n = 1159)	(n = 475)	(n = 619)
  Male, %	60	41	81	42	61	62
  Age at enrollment, median (range)	62 (29-87)	65 (24-100)	66 (28-88)	58 (45-97)	60 (32-86)	58 (37-88)
  Age at MI, median (range)	52 (27-82)	NA	57 (21-70)	NA	53 (29-77) †	NA
  Smoking, %	66	45	68	40	73	54
  Diabetes, %	20	0‡	25	0‡	38	10
  Dyslipidemia§, %	84	53	84	61	95	56
  Hypertension∥, %	61	32	66	33	96	78
  BMI (kg/m2), mean ± SD	28 ± 5	26 ± 5	28 ± 5	26 ± 5	31 ± 6	30 ± 7
  † Data available for 254 cases.
  ‡Individuals with diabetes were excluded from control group.
  §Dyslipidemia was defined in Study 1 and Study 2 to be self-reported history of a physician diagnosis of dyslipidemia or the use of lipid lowering prescription medication(s) and defined in Study 3 to be the use of lipid lowering prescription medication(s), LDL
  ∥Hypertension was defined in Study 1 and Study 2 to be a self-reported history of a physician diagnosis of hypertension or use of antihypertensive prescription medication(s) and defined in Study 3 to be the use of antihypertensive prescription medication(s), systolic blood pressure >160 mmHg, or diastolic blood pressure >90 mmHg.
  NA; not applicable.

• TABLE 12
  Twenty-four SNPs associated with MI in Study 1 and Study 2

  Study 1

  Study 2

  			Risk				Risk
  		Risk	Allele				Allele	P value
  SNP	Gene Symbol	Allele	Freq.	P value	OR	95% CI	Freq.	(1-sided)	OR	90% CI

  rs11568658	ABCC4	G	0.97	0.005	1.98	1.24-3.16	0.97	0.01	1.81	1.19-2.77
  rs16875009	ADAMTS16	A	0.13	0.005	1.33	1.09-1.62	0.13	0.005	1.29	1.10-1.51
  rs25651	ANPEP	T	0.29	0.0001	1.36	1.17-1.58	0.31	0.02	1.17	1.03-1.33
  rs439401	APOE	T	0.35	0.03	1.17	1.01-1.35	0.37	0.01	1.19	1.05-1.35
  rs867852	Clorf81	T	0.78	0.03	1.22	1.02-1.45	0.78	0.04	1.17	1.01-1.37
  rs28372907	DHX33	A	0.18	0.03	1.21	1.02-1.44	0.18	0.01	1.22	1.05-1.42
  rs11553576	EML3	T	0.60	0.03	1.17	1.02-1.35	0.60	0.03	1.16	1.02-1.31
  rs1325920	ENO1	A	0.80	0.02	1.24	1.03-1.48	0.80	0.007	1.26	1.08-1.48
  rs31208	FAM71B	G	0.11	0.03	1.27	1.03-1.57	0.12	0.006	1.30	1.09-1.55
  rs3793456	FXN	G	0.56	0.01	1.20	1.05-1.39	0.55	0.03	1.15	1.02-1.30
  rs10890	FXN	T	0.43	0.004	1.23	1.07-1.42	0.43	0.03	1.15	1.02-1.30
  rs35410698	HLA-DPB2	G	0.93	0.02	1.43	1.06-1.91	0.94	0.006	1.53	1.16-2.03
  rs1136141	HSPA8	G	0.86	0.05	1.24	1.00-1.53	0.86	0.02	1.26	1.05-1.52
  rs7928656	KCTD14	A	0.84	0.04	1.23	1.01-1.51	0.84	0.004	1.32	1.11-1.57
  rs3740918	KIRREL3	G	0.69	0.003	1.26	1.08-1.46	0.70	0.01	1.20	1.05-1.37
  rs725660	LOC388553	A	0.34	0.006	1.23	1.06-1.42	0.35	0.0009	1.26	1.12-1.43
  rs3798220	LPA	C	0.02	0.04	1.59	1.03-2.48	0.02	0.008	1.72	1.19-2.49
  rs11711953	MAP4	T	0.07	0.03	1.34	1.03-1.73	0.07	0.01	1.35	1.09-1.67
  rs4907956	OLFM3	G	0.60	0.03	1.18	1.02-1.36	0.61	0.01	1.19	1.05-1.34
  rs2290819	PTPRM	T	0.38	0.03	1.17	1.01-1.35	0.38	0.008	1.20	1.06-1.35
  rs3204635	STAC3	A	0.25	0.02	1.20	1.03-1.40	0.26	0.03	1.16	1.02-1.33
  rs1866389	THBS4	C	0.20	0.03	1.21	1.02-1.43	0.20	0.03	1.19	1.03-1.37
  rs3812475	TRMT12	T	0.50	0.03	1.16	1.01-1.34	0.52	0.04	1.13	1.01-1.28
  rs862708	ZNF304	C	0.02	0.003	1.88	1.24-2.83	0.03	0.03	1.45	1.05-2.00

• TABLE 13
  Genotypic association of five SNPs in Study 3

  SNP

  Cases

  Controls

  Age and Sex adjusted

  Fully Adjusted

  (gene symbol)	Genotype	n (%)	n (%)	OR	90% CI	P value	OR	90% CI	P value

  rs1325920	AA	327 (71)	394 (65)	1.61	0.92-2.81	0.08	1.28	0.62-2.62	0.3
  (ENO1)	GA	120 (26)	186 (31)	1.25	0.70-2.22	0.3	1.20	0.57-2.54	0.3
  	GG	14 (3)	27 (4)	ref			ref
  	Additive			1.28	1.06-1.55	0.01	1.09	0.85-1.38	0.3
  rs10890	TT	117 (25)	98 (16)	1.52	1.14-2.04	0.009	1.49	1.02-2.18	0.04
  (FXN)	CT	201 (44)	325 (54)	0.79	0.62-0.99	0.9	0.85	0.63-1.16	0.8
  	CC	143 (31)	183 (30)	ref			ref
  	Additive			1.18	1.02-1.37	0.03	1.18	0.98-1.42	0.07
  rs3793456	GG	174 (38)	180 (30)	1.33	0.98-1.80	0.06	1.50	1.01-2.22	0.04
  (FXN)	AG	205 (45)	319 (53)	0.88	0.66-1.18	0.8	1.00	0.69-1.45	0.5
  	AA	78 (17)	107 (18)	ref			ref
  	Additive			1.21	1.04-1.40	0.02	1.26	1.05-1.53	0.02
  rs35410698	GG	426 (92)	539 (89)	1.56	1.09-2.22	0.02	2.07	1.31-3.27	0.004
  (HLA-DPB2)	GA	36 (8)	70 (11)	ref			ref
  	Additive			1.46	1.03-2.06	0.04	1.79	1.14-2.81	0.02
  rs3798220	CT	41 (9)	12 (2)	4.63	2.67-8.03	<0.001	3.52	1.85-6.69	0.001
  (LPA)	TT	416 (91)	573 (98)	ref			ref
  	Additive			4.63	2.67-8.03	<0.001	3.52	1.85-6.69	0.001

• TABLE 14
  			UCSF1(S0012)

  		Non-				Case	Control
  		Risk	Risk	Case	Control	Allele	Allele
  Marker	gene	Allele	Allele	Samples**	Samples**	Freq*	Freq*	OR*	OR95L*	OR95U*	P-value*	stratum	Model
  hCV16065831	ENO1	T	C	735	854	0.55	0.51	1.15	1.00	1.33	0.051	A	additive
  hCV25996298	SLC45A1	T	G	734	855	0.82	0.80	1.16	0.97	1.39	0.095	A	additive
  hCV3086961	RERE	C	A	735	856	0.81	0.78	1.27	1.07	1.52	0.007	A	additive
  hCV3087016	RERE	C	A	736	848	0.80	0.77	1.19	1.00	1.41	0.050	A	additive
  hCV32055477	RERE	G	A	733	845	0.81	0.77	1.31	1.10	1.56	0.002	A	additive
  hCV32055625		T	C	733	852	0.82	0.78	1.26	1.05	1.50	0.011	A	additive
  hCV32055654		G	A	737	853	0.31	0.27	1.19	1.02	1.39	0.024	A	additive
  hCV8824394	RERE	T	G	736	853	0.82	0.79	1.21	1.01	1.44	0.037	A	additive
  hCV8881160	RERE	C	T	732	852	0.92	0.89	1.38	1.08	1.77	0.009	A	additive
  hCV11398434	RERE	C	T	736	854	0.81	0.77	1.28	1.07	1.52	0.006	A	additive
  hCV11398437	RERE	C	T	726	836	0.82	0.79	1.28	1.07	1.54	0.007	A	additive
  hCV1188747	RERE	G	C	737	854	0.58	0.53	1.21	1.05	1.39	0.007	A	additive
  hCV29819064	RERE	C	T	737	854	0.81	0.78	1.24	1.04	1.48	0.015	A	additive
  hCV2987229	RERE	C	T	735	853	0.55	0.52	1.15	1.00	1.32	0.054	A	additive
  hCV2987250	RERE	G	C	737	854	0.81	0.77	1.24	1.04	1.47	0.015	A	additive
  hCV30233466	RERE	G	A	736	856	0.56	0.52	1.17	1.02	1.35	0.026	A	additive
  hCV30287627	RERE	T	A	735	854	0.60	0.56	1.16	1.01	1.33	0.039	A	additive
  hCV30467730	RERE	T	C	732	855	0.80	0.76	1.25	1.05	1.49	0.011	A	additive
  hCV3086932	RERE	G	T	675	785	0.77	0.72	1.27	1.07	1.52	0.007	A	additive
  hCV3086950	RERE	A	G	737	856	0.80	0.76	1.26	1.06	1.50	0.008	A	additive
  hCV3086983	RERE	T	C	734	851	0.19	0.17	1.22	1.02	1.46	0.034	A	additive
  hCV32055474	RERE	G	C	736	852	0.81	0.77	1.28	1.07	1.52	0.006	A	additive
  hCV32055581	RERE	A	G	736	854	0.29	0.26	1.16	0.99	1.35	0.065	A	additive
  hCV32055596	RERE	G	A	735	854	0.82	0.79	1.26	1.05	1.51	0.012	A	additive
  hCV8379452		T	C	737	853	0.56	0.51	1.19	1.04	1.37	0.012	A	additive
  hCV8824244	ENO1	T	C	735	851	0.81	0.79	1.19	0.99	1.42	0.063	A	additive
  hCV8824248	ENO1	A	G	736	855	0.82	0.79	1.20	1.01	1.44	0.042	A	additive

  UCSF2(S0061)

  Case

  Control

  r2 with

  	Case	Control	Allele	Allele							hCV8824241
  Marker	Samples**	Samples**	Freq*	Freq*	OR*	OR95L*	OR95U*	P-value*	stratum	Model	(ENO1)***
  hCV16065831	558	1152	0.56	0.52	1.18	1.02	1.36	0.0225	All	additive	0.238
  hCV25996298	555	1152	0.82	0.79	1.24	1.03	1.48	0.0211	All	additive	0.214
  hCV3086961	558	1154	0.82	0.77	1.34	1.12	1.60	0.0016	All	additive	0.451
  hCV3087016	558	1145	0.81	0.77	1.26	1.06	1.51	0.0105	All	additive	0.416
  hCV32055477	555	1149	0.82	0.77	1.33	1.11	1.59	0.0019	All	additive	0.442
  hCV32055625	557	1153	0.82	0.78	1.27	1.07	1.52	0.0077	All	additive	0.596
  hCV32055654	557	1153	0.31	0.29	1.35	0.97	1.88	0.0739	All	recessive	0.059
  hCV8824394	557	1154	0.82	0.78	1.28	1.06	1.53	0.0084	All	additive	0.342
  hCV8881160	558	1152	0.91	0.89	1.30	1.02	1.65	0.0324	All	additive	0.327

  hCV11398434												0.458
  hCV11398437												0.45
  hCV1188747												0.171
  hCV29819064												0.442
  hCV2987229												0.102
  hCV2987250												0.416
  hCV30233466												0.162
  hCV30287627												0.149
  hCV30467730												0.418
  hCV3086932												0.38
  hCV3086950												0.425
  hCV3086983												0.025
  hCV32055474												0.451
  hCV32055581												0.047
  hCV32055596												0.548
  hCV8379452												0.157
  hCV8824244												0.885
  hCV8824248												0.87
  note:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  *** based on UCSF1
  Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

• TABLE 15
  			UCSF1(S0012)

  		Non				Case	Control
  		Risk	Risk	Case	Control	Allele	Allele
  Marker	gene	Allele	Allele	Samples**	Samples**	Freq*	Freq*	OR*	OR95L*	OR95U*	P-value*	stratum	Model
  hCV29033518		A	T	737	854	0.09	0.07	1.28	0.99	1.64	0.0569	additive	ALL_ALL
  hCV472000	TJP2	G	A	734	853	0.10	0.07	1.33	1.03	1.70	0.0263	additive	ALL_ALL
  hCV28008078	FXN	C	T	735	855	0.58	0.54	1.18	1.02	1.35	0.0219	additive	ALL_ALL
  hCV30586985	FXN	A	G	736	855	0.60	0.55	1.23	1.06	1.41	0.0047	additive	ALL_ALL
  hCV27970553	TJP2	T	C	731	850	0.43	0.40	1.17	1.01	1.35	0.0344	additive	ALL_ALL
  hCV7442005	TJP2	G	A	737	851	0.49	0.44	1.22	1.06	1.40	0.0065	additive	ALL_ALL
  hCV1463112		C	T	734	853	0.59	0.55	1.16	1.01	1.34	0.0333	additive	ALL_ALL
  hCV15892430	FXN	C	T	731	849	0.56	0.51	1.23	1.07	1.42	0.0038	additive	ALL_ALL
  hCV1463224	FXN	T	C	737	854	0.49	0.43	1.25	1.08	1.44	0.0022	additive	ALL_ALL
  hCV1463222	FXN	C	T	730	856	0.49	0.43	1.26	1.10	1.46	0.0011	additive	ALL_ALL
  hCV11761245	TJP2	C	T	735	855	0.48	0.43	1.21	1.05	1.39	0.0071	additive	ALL_ALL
  hCV1463184	FXN	T	C	735	853	0.81	0.79	1.73	1.06	2.83	0.0289	dominant	ALL_ALL
  hCV1844077	TJP2	G	A	736	855	0.75	0.72	1.19	0.98	1.45	0.0863	recessive	ALL ALL

  UCSF2(S0061)

  			Case	Control							r2 with
  	Case	Control	Allele	Allele							hCV1463226
  Marker	Samples**	Samples**	Freq*	Freq*	OR*	OR95L*	OR95U*	P-value*	stratum	Model	(FXN) ***
  hCV29033518	558	1152	0.10	0.08	1.23	0.96	1.58	0.0977	add	ALL_ALL	0.042
  hCV472000	557	1150	0.09	0.07	1.30	0.98	1.71	0.0653	dom	ALL_ALL	0.057
  hCV28008078											0.446
  hCV30586985											0.572
  hCV27970553											0.237
  hCV7442005											0.325
  hCV1463112											0.411
  hCV15892430											0.435
  hCV1463224											0.99
  hCV1463222											0.989
  hCV11761245											0.343
  hCV1463184											0.196
  hCV1844077											0
  note:
  *allele frequency, OR, and p-value are tor the risk allele
  **valid counts tor each SNP
  *** based on UCSF1
  Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

• TABLE 16
  UCSF1

  					Case	Control	Case Allele
  marker	rs	Gene	RiskAllele	NonRiskAllele	Samples**	Samples**	Freq*
  hCV1188731	rs4908514	RERE	T	C	730	793	0.82
  hCV1188735	rs10864366	RERE	C	T	734	793	0.82
  hCV15967490	rs2292242	SLC45A1	T	C	728	795	0.59
  hCV27157435	rs7513420	RERE	C	T	735	794	0.60
  hCV27157439	rs10779704	RERE	C	A	729	783	0.60
  hCV27884601	rs4908776	RERE	C	T	734	793	0.82
  hCV27958354	rs4908762	RERE	T	C	731	794	0.80
  hCV28023091	rs4908773	RERE	C	T	736	792	0.83
  hCV29368919	rs4908513	RERE	C	T	729	796	0.83
  hCV2966448	rs1064826	RERE	A	G	734	790	0.28
  hCV29873524	rs7533113	RERE	T	C	725	793	0.82
  hCV29945430	rs7517436	RERE	T	G	734	789	0.82
  hCV3086948	rs10864361	RERE	C	T	734	794	0.59
  hCV3087000	rs1463055	RERE	A	G	736	796	0.81
  hCV3087003	rs6577500	RERE	C	G	734	793	0.80
  hCV3087008	rs12136689	RERE	C	A	723	794	0.33
  hCV3087015	rs11121198	RERE	G	C	735	792	0.81
  hCV32055527	rs10864364	RERE	A	C	736	795	0.83
  hCV32055595	rs6577524	RERE	T	C	734	792	0.83
  hCV529178	rs301811	RERE	T	C	732	789	0.81
  hCV597227	rs301809	RERE	T	C	736	793	0.81
  hCV8823713	rs1472228	RERE	T	C	736	791	0.82
  hCV8824424	rs1058790	RERE	A	G	735	793	0.82
  hCV8824425	rs1058791	RERE	A	C	723	792	0.82
  hCV8824453	rs1466654	SLC45A1	T	G	732	790	0.57
  hCV8881161	rs926951	RERE	G	A	734	789	0.80
  hCV8881164	rs1150398	RERE	T	C	733	786	0.98

  	Control							r{circumflex over ( )}2 with
  	Allele							hCV32055477
  marker	Freq*	OR*	OR95L*	OR95U*	P_value	Strata	Model	(RERE)
  hCV1188731	0.79	1.26	1.05	1.51	0.0141	AllvsAll	add	0.689
  hCV1188735	0.79	1.25	1.05	1.50	0.0148	AllvsAll	add	0.705
  hCV15967490	0.56	1.17	1.01	1.35	0.0367	AllvsAll	add	0.167
  hCV27157435	0.57	1.17	1.01	1.35	0.0351	AllvsAll	add	0.358
  hCV27157439	0.57	1.17	1.01	1.35	0.0369	AllvsAll	add	0.35
  hCV27884601	0.79	1.25	1.05	1.51	0.0148	AllvsAll	add	0.64
  hCV27958354	0.77	1.23	1.03	1.46	0.0207	AllvsAll	add	0.896
  hCV28023091	0.79	1.31	1.09	1.57	0.0044	AllvsAll	add	0.714
  hCV29368919	0.79	1.28	1.06	1.53	0.0087	AllvsAll	add	0.691
  hCV2966448	0.25	1.15	0.98	1.35	0.0971	AllvsAll	add	0.071
  hCV29873524	0.79	1.27	1.05	1.52	0.0117	AllvsAll	add	0.701
  hCV29945430	0.78	1.28	1.07	1.53	0.0076	AllvsAll	add	0.641
  hCV3086948	0.56	1.15	1.00	1.33	0.0496	AllvsAll	add	0.345
  hCV3087000	0.77	1.26	1.06	1.50	0.0096	AllvsAll	add	0.897
  hCV3087003	0.77	1.23	1.03	1.46	0.0202	AllvsAll	add	0.907
  hCV3087008	0.29	1.15	0.99	1.35	0.0673	AllvsAll	add	0.106
  hCV3087015	0.77	1.25	1.05	1.49	0.0125	AllvsAll	add	0.901
  hCV32055527	0.79	1.29	1.07	1.54	0.0067	AllvsAll	add	0.699
  hCV32055595	0.79	1.26	1.05	1.51	0.0149	AllvsAll	add	0.693
  hCV529178	0.77	1.23	1.04	1.47	0.0178	AllvsAll	add	0.895
  hCV597227	0.77	1.26	1.06	1.50	0.0096	AllvsAll	add	0.897
  hCV8823713	0.79	1.23	1.02	1.47	0.0276	AllvsAll	add	0.698
  hCV8824424	0.79	1.23	1.03	1.47	0.0230	AllvsAll	add	0.444
  hCV8824425	0.79	1.20	1.00	1.44	0.0441	AllvsAll	add	0.435
  hCV8824453	0.53	1.19	1.03	1.37	0.0187	AllvsAll	add	0.149
  hCV8881161	0.77	1.24	1.04	1.47	0.0167	AllvsAll	add	0.889
  hCV8881164	0.97	1.53	0.94	2.48	0.0848	AllvsAll	add	0.088
  notes:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  Study design in UCSF1: MI cases vs No CHD controls

• TABLE 17
  UCSF1

  							Case
  					Case	Control	Allele
  marker	rs	Gene	RiskAllele	NonRiskAllele	Samples**	Samples**	Freq*
  hCV28993059	rs4832179		A	G	770	920	0.09
  hCV2091649	rs12714147	VAMP5	G	A	771	921	0.17
  hCV8696079	rs960066		T	G	723	864	0.21
  hCV2091650	rs10206961	RNF181	T	C	723	862	0.42
  hCV11504800	rs10176176		T	A	721	861	0.48
  hCV8696050	rs1254901	VAMP8	G	A	770	920	0.70
  hCV11942442	rs1254898	GGCX	C	T	718	862	0.70
  hCV2091669	rs11688233		T	A	723	865	0.92
  hCV2091674	rs6733550	TMEM150	G	T	716	862	0.37

  	Control							r{circumflex over ( )}2 with
  	Allele							hCV2091644
  marker	Freq*	OR*	OR95L*	OR95U*	P value	Strata	Model	(VAMPS)
  hCV28993059	0.08	1.25	0.99	1.58	0.0653	All	add	0.019
  hCV2091649	0.15	1.17	0.97	1.41	0.0935	All	add	0.277
  hCV8696079	0.19	1.16	0.97	1.37	0.0986	All	add	0.219
  hCV2091650	0.39	1.14	0.99	1.31	0.0706	All	add	0.648
  hCV11504800	0.44	1.17	1.02	1.35	0.0291	All	add	0.784
  hCV8696050	0.66	1.22	1.06	1.41	0.0072	All	add	0.323
  hCV11942442	0.66	1.18	1.02	1.38	0.0272	All	add	0.307
  hCV2091669	0.90	1.39	1.08	1.78	0.0102	All	add	0.064
  hCV2091674	0.34	1.14	0.99	1.33	0.0755	All	add	0.364
  notes:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  Study design in UCSF1: MI cases vs No CHD controls

• TABLE 18
  UCSF1

  							Case
  					Case	Control	Allele
  marker	rs	Gene	RiskAllele	NonRiskAllele	Samples**	Samples**	Freq*
  hCV11846435	rs6929299	LPA	T	C	760	852	0.67
  hCV207123	rs7771801	LPA	C	G	757	855	0.68
  hCV25927459	rs3798221	LPA	G	T	752	855	0.83
  hCV27462774	rs3127583		A	G	735	797	0.16
  hCV282793	rs11751605	LPA	C	T	761	855	0.16
  hCV29322781	rs6921516	LPA	G	A	734	795	0.68
  hCV29809835	rs9457880		A	C	735	796	0.05
  hCV29952522	rs9457931	LPAL2	G	A	733	797	0.08
  hCV30574599	rs7770628	LPA	C	T	728	794	0.49
  hCV3201490	rs1321195	LPA	G	A	735	795	0.87
  hCV334752	rs6939089	LPA	T	C	758	853	0.68
  hDV70715669	rs16891445		T	A	735	795	0.05
  hDV70973697	rs17593921	SLC22A3	C	T	735	796	0.98
  hCV31161091	rs3127573	SLC22A2	G	A	733	788	0.13
  hCV1550877	rs6919346	LPA	C	T	759	851	0.85
  hCV2335281	rs519118	SLC22A3	T	G	733	796	0.54
  hCV3111822	rs316025	SLC22A2	T	C	735	794	0.28
  hCV561574	rs624319	SLC22A3	G	A	733	796	0.55

  	Control							r{circumflex over ( )}2 with
  	Allele							hCV25930271
  marker	Freq*	OR*	OR95L*	OR95U*	P value	Strata	Model	(LPA)
  hCV11846435	0.61	1.26	1.09	1.46	0.0018	All	add	0.01
  hCV207123	0.63	1.24	1.07	1.44	0.0038	All	add	0.009
  hCV25927459	0.79	1.28	1.07	1.53	0.0058	All	add	0.004
  hCV27462774	0.13	1.26	1.02	1.54	0.0304	All	add	0.004
  hCV282793	0.14	1.19	0.98	1.43	0.0780	All	add	0.005
  hCV29322781	0.63	1.24	1.07	1.45	0.0044	All	add	0.008
  hCV29809835	0.04	1.37	0.96	1.96	0.0828	All	add	0
  hCV29952522	0.06	1.52	1.15	2.01	0.0030	All	add	0.352
  hCV30574599	0.45	1.17	1.02	1.35	0.0281	All	add	0.014
  hCV3201490	0.85	1.26	1.02	1.54	0.0292	All	add	0.004
  hCV334752	0.63	1.24	1.08	1.44	0.0032	All	add	0.009
  hDV70715669	0.04	1.46	1.02	2.08	0.0378	All	add	0
  hDV70973697	0.97	1.62	1.01	2.61	0.0475	All	add	0
  hCV31161091	0.11	1.27	1.00	1.61	0.0541	All	dom	0.004
  hCV1550877	0.83	1.24	1.00	1.53	0.0519	All	rec	0.004
  hCV2335281	0.52	1.29	1.03	1.61	0.0284	All	rec	0.021
  hCV3111822	0.26	1.42	0.95	2.12	0.0857	All	rec	0.005
  hCV561574	0.52	1.29	1.03	1.61	0.0276	All	rec	0.021
  notes:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  Study design in UCSF1: Ml cases vs No CHD controls

• TABLE 19
  Meta-analysis of UCSF1 and UCSF2

  myocardial infarction (MI) risk

  Non-

  Case

  Control

  			Risk	Risk	Case	Control	Allele	Allele
  marker	Gene	Chr	Allele	Allele	Samples**	Samples**	Freq*	Freq*	OR*	95% CI*
  hCV11846435	LPA	6	T	C	1329	1994	0.67	0.63	1.22	1.10-1.36
  hCV1550877	LPA	6	C	T	1327	2003	0.84	0.82	1.17	1.02-1.34
  hCV207123	LPA	6	C	G	1331	2010	0.68	0.65	1.17	1.05-1.30
  hCV2335281	SLC22A3	6	T	G	1306	1952	0.53	0.51	1.19	1.01-1.39
  hCV25927459	LPA	6	G	T	1325	2008	0.82	0.80	1.16	1.02-1.32
  hCV25930271	LPA	6	C	T	1338	2015	0.03	0.02	1.66	1.21-2.26
  hCV27422538	LPA	6	C	G	1335	2015	0.80	0.77	1.25	1.10-1.41
  hCV27462774		6	A	G	1308	1954	0.15	0.13	1.18	1.03-1.36
  hCV282793	LPA	6	C	T	1334	2010	0.16	0.14	1.20	1.04-1.37
  hCV29322781	LPA	6	G	A	1307	1949	0.68	0.65	1.16	1.04-1.29
  hCV29952522	LPAL2	6	G	A	1307	1952	0.08	0.06	1.36	1.12-1.65
  hCV30574599	LPA	6	C	T	1298	1944	0.48	0.46	1.09	0.99-1.21
  hCV3111822	SLC22A2	6	T	C	1308	1949	0.28	0.26	1.12	1.00-1.25
  hCV31161091	SLC22A2	6	G	A	1307	1942	0.13	0.11	1.20	1.03-1.39
  hCV3201490	LPA	6	G	A	1308	1951	0.88	0.85	1.27	1.09-1.47
  hCV334752	LPA	6	T	C	1328	2006	0.68	0.64	1.17	1.06-1.30
  hCV561574	SLC22A3	6	G	A	1307	1951	0.54	0.52	1.10	0.99-1.21
  hDV70973697	SLC22A3	6	C	T	1308	1951	0.98	0.97	1.31	0.96-1.78

  myocardial infarction (MI) risk

  Lp(a) level

  marker	P value*	Strata	Model	Samples**	Estimate*	95% CI*	P value*	Strata	Model
  hCV11846435	0.0001	AllvsAll	add	911	0.122	0.06-0.19	1.95E−04	AllvsAll	add
  hCV1550877	0.0203	AllvsAll	add	914	0.190	0.11-0.27	2.73E−06	AllvsAll	add
  hCV207123	0.0034	AllvsAll	add	915	0.076	0.01-0.14	0.0213	AllvsAll	add
  hCV2335281	0.0324	AllvsAll	rec	892	0.093	0.03-0.15	0.0028	AllvsAll	add
  hCV25927459	0.0198	AllvsAll	add	911	0.214	0.14-0.29	4.53E−08	AllvsAll	add
  hCV25930271	0.0015	AllvsAll	add	916	0.706	0.51-0.91	7.59E−12	AllvsAll	add
  hCV27422538	0.0004	AllvsAll	add	917	0.236	0.16-0.31	3.63E−10	AllvsAll	add
  hCV27462774	0.0214	AllvsAll	add	893	0.164	0.07-0.26	5.34E−04	AllvsAll	add
  hCV282793	0.0106	AllvsAll	add	915	0.148	0.06-0.24	0.0012	AllvsAll	add
  hCV29322781	0.0063	AllvsAll	add	892	0.076	0.01-0.14	0.0239	AllvsAll	add
  hCV29952522	0.0020	AllvsAll	add	892	0.308	0.18-0.44	3.07E−06	AllvsAll	add
  hCV30574599	0.0824	AllvsAll	add	887	0.089	0.03-0.15	0.0050	AllvsAll	add
  hCV3111822	0.0496	AllvsAll	add	892	0.070	0.00-0.14	0.0562	AllvsAll	add
  hCV31161091	0.0202	AllvsAll	add	889	0.126	0.03-0.22	0.0127	AllvsAll	add
  hCV3201490	0.0016	AllvsAll	add	893	0.233	0.14-0.32	4.54E−07	AllvsAll	add
  hCV334752	0.0029	AllvsAll	add	911	0.073	0.01-0.14	0.0274	AllvsAll	add
  hCV561574	0.0676	AllvsAll	add	891	0.099	0.04-0.16	0.0013	AllvsAll	add
  hDV70973697	0.0930	AllvsAll	add	891	0.210	0.04-0.38	0.0177	AllvsAll	add
  note:
  *Data for allele frequency, OR and P-value were provided for risk alleles in this table
  **Valid counts for each SNP
  Study design for MI endpoint: MI cases vs controls having no history of CHD in UCSF1 and UCSF2
  Study design for Lp(a) level endpoint all patients with available Lp(a) level in UCSF1 and UCSF2; Lp(a) level was transformed to Log10Lp(a)

• TABLE 20
  					UCSF1(S0012)

  			Non				Case	Control
  			Allele	Risk	Case	Control	Allele	Allele
  Marker	Gene	chr	Risk	Allele	Samples**	Samples**	Freq*	Freq*	OR*	95% CI*	P-value*
  hCV22274679	TRMT12	8	C	T	737	853	0.54	0.50	1.16	(1.01-1.34)	0.0344
  hCV11688401	OR2H1	6	G	A	736	854	0.27	0.24	1.15	(0.98-1.35)	0.0833
  hDV70661573	ADAMTS1	5	T	A	710	826	0.17	0.13	1.33	(1.09-1.62)	0.0048
  hCV11854426	KCNB2	8	T	C	737	856	0.13	0.11	1.21	(0.97-1.50)	0.0837
  hCV2531730	CHKB	22	A	T	732	851	0.41	0.38	1.15	(1.00-1.33)	0.0532
  hCV3259235	EIF4E3	3	A	G	732	848	0.12	0.10	1.23	(0.99-1.53)	0.0640
  hCV904974		19	C	T	729	852	0.39	0.35	1.17	(1.01-1.35)	0.0325
  hDV68873046	C20orf23	20	A	T	736	852	0.98	0.97	1.70	(1.09-2.66)	0.0204

  UCSF2(S0061)

  Case

  Control

  UCSF1(S0012)

  Case

  Control

  Allele

  Allele

  Marker	stratum	Model	Samples**	Samples**	Freq*	Freq*	OR*	95% CI*	P-value*	stratum	Model
  hCV22274679	All	additive	574	1157	0.55	0.52	1.13	(0.98- 1.30)	0.0832	All	additive
  hCV11688401	All	additive	558	1154	0.26	0.23	1.21	(0.98-1.48)	0.0705	All	dominant
  hDV70661573	All	additive	558	1153	0.17	0.13	1.29	(1.06- 1.56)	0.0102	All	additive
  hCV11854426	All	additive	553	1138	0.14	0.12	1.22	(0.97-1.55)	0.0918	All	dominant
  hCV2531730	All	additive	557	1154	0.41	0.38	1.15	(0.99- 1.33)	0.0659	All	additive
  hCV3259235	All	additive	557	1152	0.12	0.10	1.21	(0.96- 1.52)	0.0996	All	additive
  hCV904974	All	additive	558	1151	0.41	0.37	1.19	(1.03- 1.38)	0.0200	All	additive
  hDV68873046	All	additive	558	1154	0.98	0.97	1.52	(0.95 - 2.44)	0.0815	All	additive
  notes:
  *allele frequency, OR, and p-value are for the risk allele
  **valid counts for each SNP
  Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

• TABLE 21
  CHD Risk Reduction by Pravastatin in CARE According to SNP Genotypes

  EVENTS

  NONEVENT

  EVENTS

  NONEVENT

  Gene

  (Pravastatin

  (Pravastatin

  (placebo

  (placebo

  P

  Allele

  Allele1

  Allele

  Allele2

  SNP

  rs

  symbol

  End point

  Strata

  arm)

  arm)

  arm)

  arm)

  P value

  HR

  HR95L

  HR95U

  interaction

  1

  Freq.

  2

  Freq.

  hCV16189421	rs1048755	ATXN3	endpt1	TC+TT	65	526	62	496	0.9853	1	0.708	1.421	0.0830	T	0.24	C	0.76
  hCV16189421	rs1048755	ATXN3	endpt1	CC	68	729	97	684	0.0101	0.67	0.488	0.907	0.0830	T	0.24	C	0.76
  hCV25630686		PSMB9	endpt1	TC+TT	5	85	14	78	0.0453	0.35	0.127	0.978	0.0993	T	0.03	C	0.97
  hCV25630686		PSMB9	endpt1	CC	128	1206	151	1134	0.0728	0.81	0.637	1.02	0.0993	T	0.03	C	0.97
  hCV25631989	rs1135983	ATF6	endpt1	TC+TT	26	198	13	187	0.0761	1.83	0.939	3.555	0.0080	T	0.08	C	0.92
  hCV25631989	rs1135983	ATF6	endpt1	CC	107	1044	145	1001	0.0099	0.72	0.561	0.924	0.0080	T	0.08	C	0.92
  hCV25644901		ITGA9	endpt1	GA+GG	9	120	26	103	0.0029	0.32	0.148	0.674	0.0093	G	0.05	A	0.95
  hCV25644901		ITGA9	endpt1	AA	124	1171	139	1111	0.2050	0.86	0.671	1.089	0.0093	G	0.05	A	0.95
  hCV25651076	rs5743291	NOD2	endpt1	AG+AA	28	217	21	195	0.5467	1.19	0.676	2.096	0.0926	A	0.09	G	0.91
  hCV25651076	rs5743291	NOD2	endpt1	GG	104	1068	144	1021	0.0061	0.7	0.546	0.904	0.0926	A	0.09	G	0.91
  hCV25651174	rs9277356	HLA-DPB1	endpt1	GA+GG	76	641	79	625	0.7173	0.94	0.689	1.293	0.0684	G	0.30	A	0.70
  hCV25651174	rs9277356	HLA-DPB1	endpt1	AA	57	643	86	585	0.0046	0.62	0.441	0.861	0.0684	G	0.30	A	0.70
  hCV25767417	rs3803430	ALDH1A3	endpt1	GA+GG	3	52	14	67	0.0565	0.3	0.085	1.034	0.0897	G	0.02	A	0.98
  hCV25767417	rs3803430	ALDH1A3	endpt1	AA	130	1239	151	1145	0.0703	0.81	0.637	1.018	0.0897	G	0.02	A	0.98
  hCV25922320	rs12360861	CD6	endpt1	AG+AA	62	439	56	466	0.4063	1.17	0.812	1.673	0.0033	A	0.21	G	0.79
  hCV25922320	rs12360861	CD6	endpt1	GG	70	850	109	745	0.0003	0.58	0.428	0.781	0.0033	A	0.21	G	0.79
  hCV25922440	rs34362748	GALC	endpt1	TC+TT	30	377	50	341	0.0139	0.57	0.36	0.891	0.0728	T	0.16	C	0.84
  hCV25922440	rs34362748	GALC	endpt1	CC	103	881	109	849	0.5029	0.91	0.697	1.194	0.0728	T	0.16	C	0.84
  hCV25922816	rs36013429	PPOX	endpt1	AG+AA	14	184	27	145	0.0118	0.44	0.229	0.832	0.0487	A	0.07	G	0.93
  hCV25922816	rs36013429	PPOX	endpt1	GG	119	1075	134	1045	0.2573	0.87	0.677	1.11	0.0487	A	0.07	G	0.93
  hCV25926178	rs12882130	MARK3	endpt1	GC+GG	80	786	111	714	0.0060	0.67	0.502	0.891	0.0710	G	0.38	C	0.62
  hCV25926178	rs12882130	MARK3	endpt1	CC	52	478	50	477	0.8351	1.04	0.707	1.536	0.0710	G	0.38	C	0.62
  hCV25926771	rs4906321	MARK3	endpt1	CT+CC	79	778	114	711	0.0035	0.65	0.49	0.869	0.0316	C	0.31	T	0.69
  hCV25926771	rs4906321	MARK3	endpt1	TT	53	482	47	478	0.6009	1.11	0.75	1.645	0.0316	C	0.31	T	0.69
  hCV25927605		HLA-DPA1	endpt1	TC+TT	10	80	3	74	0.1082	2.88	0.792	10.466	0.0216	T	0.03	C	0.97
  hCV25927605		HLA-DPA1	endpt1	CC	122	1206	162	1136	0.0067	0.72	0.571	0.914	0.0216	T	0.03	C	0.97
  hCV25928135		ADAM12	endpt1	CT+CC	41	479	63	430	0.0091	0.59	0.4	0.878	0.0741	C	0.21	T	0.79
  hCV25928135		ADAM12	endpt1	TT	92	785	97	756	0.5831	0.92	0.694	1.228	0.0741	C	0.21	T	0.79
  hCV25941408	rs28497577	MYLK	endpt1	TG+TT	18	238	38	208	0.0035	0.43	0.248	0.761	0.0191	T	0.10	G	0.90
  hCV25941408	rs28497577	MYLK	endpt1	GG	115	1052	125	1010	0.3660	0.89	0.691	1.146	0.0191	T	0.10	G	0.90
  hCV25942539	rs2401751	PTPN21	endpt1	AG+AA	63	700	98	682	0.0067	0.65	0.47	0.886	0.0496	A	0.34	G	0.66
  hCV25942539	rs2401751	PTPN21	endpt1	GG	70	559	62	511	0.8839	1.03	0.729	1.444	0.0496	A	0.34	G	0.66
  hCV26000635	rs7020782	PAPPA	endpt1	CA+CC	82	665	84	645	0.8006	0.96	0.709	1.304	0.0322	C	0.31	A	0.69
  hCV26000635	rs7020782	PAPPA	endpt1	AA	51	624	81	566	0.0024	0.58	0.409	0.824	0.0322	C	0.31	A	0.69
  hCV2633049	rs2302006	CCL24	endpt1	GT+GG	48	440	47	443	0.8749	1.03	0.691	1.544	0.0812	G	0.20	T	0.81
  hCV2633049	rs2302006	CCL24	endpt1	TT	85	849	117	771	0.0050	0.67	0.507	0.887	0.0812	G	0.20	T	0.81
  hCV2658421	rs3176975	APOH	endpt1	AC+AA	48	522	80	494	0.0037	0.59	0.412	0.842	0.0496	A	0.23	C	0.77
  hCV2658421	rs3176975	APOH	endpt1	CC	84	769	84	718	0.6671	0.94	0.692	1.266	0.0496	A	0.23	C	0.77
  hCV2741051	rs2230806	ABCA1	endpt1	TC+TT	66	645	62	593	0.9717	0.99	0.703	1.406	0.0576	T	0.28	C	0.72
  hCV2741051	rs2230806	ABCA1	endpt1	CC	67	647	103	624	0.0038	0.63	0.467	0.864	0.0576	T	0.28	C	0.72
  hCV2741083	rs4149313	ABCA1	endpt1	CT+CC	36	316	23	289	0.2143	1.39	0.826	2.351	0.0119	C	0.13	T	0.87
  hCV2741083	rs4149313	ABCA1	endpt1	TT	97	976	142	927	0.0020	0.67	0.515	0.862	0.0119	C	0.13	T	0.87
  hCV2932115	rs5517	KLK1	endpt1	CT+CC	75	591	77	566	0.7201	0.94	0.687	1.297	0.0755	C	0.27	T	0.73
  hCV2932115	rs5517	KLK1	endpt1	TT	58	701	88	651	0.0050	0.62	0.447	0.867	0.0755	C	0.27	T	0.73
  hCV2983035	rs9527026	KL	endpt1	AG+AA	36	387	53	321	0.0110	0.58	0.378	0.882	0.0944	A	0.15	G	0.85
  hCV2983035	rs9527026	KL	endpt1	GG	97	903	110	893	0.3656	0.88	0.671	1.158	0.0944	A	0.15	G	0.85
  hCV3026189	rs11739136	KCNIP1	endpt1	TC+TT	29	241	23	234	0.4448	1.24	0.716	2.14	0.0557	T	0.10	C	0.90
  hCV3026189	rs11739136	KCNIP1	endpt1	CC	104	1050	142	984	0.0048	0.69	0.54	0.895	0.0557	T	0.10	C	0.90
  hCV3068176	rs1801394	MTRR	endpt1	AG+AA	100	908	110	873	0.3839	0.89	0.676	1.162	0.0609	A	0.46	G	0.54
  hCV3068176	rs1801394	MTRR	endpt1	GG	33	384	55	345	0.0062	0.55	0.355	0.842	0.0609	A	0.46	G	0.54
  hCV3111721	rs33950747	NPHS1	endpt1	TC+TT	11	191	19	126	0.0160	0.4	0.191	0.844	0.0645	T	0.06	C	0.94
  hCV3111721	rs33950747	NPHS1	endpt1	CC	121	1098	146	1088	0.1265	0.83	0.651	1.055	0.0645	T	0.06	C	0.94
  hCV529706	rs428785	ADAMTS1	endpt1	CG+CC	55	569	80	476	0.0036	0.6	0.426	0.846	0.0611	C	0.24	G	0.76
  hCV529706	rs428785	ADAMTS1	endpt1	GG	77	719	84	735	0.6603	0.93	0.685	1.271	0.0611	C	0.24	G	0.76
  hCV529710	rs402007	ADAMTS1	endpt1	CG+CC	57	570	81	480	0.0052	0.62	0.44	0.866	0.0858	C	0.24	G	0.76
  hCV529710	rs402007	ADAMTS1	endpt1	GG	76	720	84	737	0.6155	0.92	0.677	1.26	0.0858	C	0.24	G	0.76
  hCV5478	rs1800574	TCF1	endpt1	TC+TT	11	75	4	76	0.0953	2.65	0.843	8.319	0.0175	T	0.03	C	0.97
  hCV5478	rs1800574	TCF1	endpt1	CC	122	1217	161	1141	0.0067	0.72	0.571	0.914	0.0175	T	0.03	C	0.97
  hCV549926	rs1057141	Tap1or	endpt1	CT+CC	33	395	58	354	0.0042	0.54	0.35	0.822	0.0495	C	0.16	T	0.84
  hCV549926	rs1057141	Tap1or	endpt1	TT	99	894	107	857	0.3934	0.89	0.675	1.167	0.0495	C	0.16	T	0.84
  hCV594695	rs45551939	SERPINA1	endpt1	AT+AA	19	115	11	92	0.3548	1.42	0.675	2.997	0.0813	A	0.04	T	0.96
  hCV594695	rs45551939	SERPINA1	endpt1	TT	112	1169	154	1121	0.0055	0.71	0.555	0.904	0.0813	A	0.04	T	0.96
  hCV598677	rs5370	EDN1	endpt1	TG+TT	44	518	70	459	0.0035	0.57	0.391	0.831	0.0339	T	0.22	G	0.78
  hCV598677	rs5370	EDN1	endpt1	GG	89	774	93	759	0.7179	0.95	0.709	1.268	0.0339	T	0.22	G	0.78
  hCV7441704	rs1800205	PPT1	endpt1	GA+GG	7	118	18	109	0.0354	0.39	0.164	0.938	0.0966	G	0.05	A	0.95
  hCV7441704	rs1800205	PPT1	endpt1	AA	125	1169	147	1107	0.0868	0.81	0.64	1.031	0.0966	G	0.05	A	0.95
  hCV7443062	rs897453	PEMT	endpt1	TC+TT	102	897	107	865	0.5540	0.92	0.702	1.208	0.0186	T	0.45	C	0.55
  hCV7443062	rs897453	PEMT	endpt1	CC	31	395	57	350	0.0021	0.5	0.325	0.78	0.0186	T	0.45	C	0.55
  hCV7475492	rs1138469	HSPG2	endpt1	TC+TT	23	156	22	185	0.5131	1.22	0.677	2.181	0.0988	T	0.07	C	0.93
  hCV7475492	rs1138469	HSPG2	endpt1	CC	109	1132	142	1026	0.0072	0.71	0.553	0.912	0.0988	T	0.07	C	0.93
  hCV7490135	rs1805082	NPC1	endpt1	CT+CC	85	924	126	866	0.0018	0.64	0.49	0.849	0.0207	C	0.47	T	0.53
  hCV7490135	rs1805082	NPC1	endpt1	TT	48	363	39	345	0.4748	1.17	0.765	1.78	0.0207	C	0.47	T	0.53
  hCV7494810	rs1058587	GDF15	endpt1	GC+GG	46	559	80	517	0.0017	0.56	0.389	0.804	0.0241	G	0.25	C	0.75
  hCV7494810	rs1058587	GDF15	endpt1	CC	86	730	85	697	0.7657	0.96	0.708	1.289	0.0241	G	0.25	C	0.75
  hCV7499212	rs1800127	LRP1	endpt1	TC+TT	5	63	14	56	0.0366	0.34	0.121	0.934	0.0831	T	0.02	C	0.98
  hCV7499212	rs1800127	LRP1	endpt1	CC	128	1229	151	1158	0.0771	0.81	0.639	1.023	0.0831	T	0.02	C	0.98
  hCV7514879	rs1800629		endpt1	AG+AA	33	403	55	361	0.0048	0.54	0.348	0.827	0.0538	A	0.17	G	0.83
  hCV7514879	rs1800629		endpt1	GG	100	885	110	855	0.4029	0.89	0.679	1.168	0.0538	A	0.17	G	0.83
  hCV7577801	rs11876	SLC9A3R2	endpt1	TC+TT	56	491	48	468	0.6023	1.11	0.753	1.629	0.0200	T	0.22	C	0.78
  hCV7577801	rs11876	SLC9A3R2	endpt1	CC	77	798	117	741	0.0015	0.63	0.471	0.837	0.0200	T	0.22	C	0.78
  hCV7618856	rs1143675	ITGA4	endpt1	CT+CC	4	19	1	33	0.0972	6.39	0.714	57.205	0.0287	C	0.01	T	0.99
  hCV7618856	rs1143675	ITGA4	endpt1	TT	127	1264	163	1182	0.0114	0.74	0.588	0.935	0.0287	C	0.01	T	0.99
  hCV783138	rs6046	F10	endpt1	AG+AA	31	258	24	242	0.4753	1.21	0.713	2.069	0.0600	A	0.11	G	0.89
  hCV783138	rs6046	F10	endpt1	GG	101	1033	139	972	0.0051	0.69	0.537	0.896	0.0600	A	0.11	G	0.89
  hCV783184	rs510335		endpt1	TG+TT	32	282	27	273	0.5952	1.15	0.688	1.918	0.0802	T	0.12	G	0.88
  hCV783184	rs510335		endpt1	GG	100	1008	137	942	0.0053	0.69	0.536	0.897	0.0802	T	0.12	G	0.88
  hCV7841642	rs11666735	FCAR	endpt1	AG+AA	13	183	30	169	0.0103	0.43	0.222	0.817	0.0473	A	0.07	G	0.93
  hCV7841642	rs11666735	FCAR	endpt1	GG	120	1108	135	1048	0.1808	0.85	0.661	1.081	0.0473	A	0.07	G	0.93
  hCV7900503	rs3732379	CX3CR1	endpt1	TC+TT	65	614	68	616	0.7875	0.95	0.679	1.341	0.0908	T	0.28	C	0.72
  hCV7900503	rs3732379	CX3CR1	endpt1	CC	68	677	97	600	0.0051	0.64	0.471	0.875	0.0908	T	0.28	C	0.72
  hCV795441	rs401502	IL12RB1	endpt1	GC+GG	81	690	79	649	0.8725	0.97	0.715	1.329	0.0296	G	0.32	C	0.68
  hCV795441	rs401502	IL12RB1	endpt1	CC	52	596	86	565	0.0022	0.58	0.414	0.825	0.0296	G	0.32	C	0.68
  hCV795442	rs375947	IL12RB1	endpt1	GA+GG	80	691	77	651	0.9472	0.99	0.724	1.353	0.0218	G	0.32	A	0.68
  hCV795442	rs375947	IL12RB1	endpt1	AA	52	599	87	566	0.0016	0.58	0.408	0.812	0.0218	G	0.32	A	0.68
  hCV8705506	rs5516	KLK1	endpt1	CG+CC	66	749	96	667	0.0032	0.62	0.456	0.854	0.0480	C	0.34	G	0.66
  hCV8705506	rs5516	KLK1	endpt1	GG	67	543	69	550	0.9467	0.99	0.706	1.384	0.0480	C	0.34	G	0.66
  hCV8708474	rs1800468	MGC4093	endpt1	TC+TT	30	212	23	194	0.5341	1.19	0.69	2.046	0.0851	T	0.09	C	0.91
  hCV8708474	rs1800468	MGC4093	endpt1	CC	103	1068	142	1013	0.0062	0.7	0.545	0.905	0.0851	T	0.09	C	0.91
  hCV8718197	rs1050998	CXCL16	endpt1	GA+GG	98	879	100	842	0.6535	0.94	0.71	1.24	0.0102	G	0.44	A	0.56
  hCV8718197	rs1050998	CXCL16	endpt1	AA	33	409	65	376	0.0008	0.49	0.322	0.744	0.0102	G	0.44	A	0.56
  hCV8726337	rs5498	ICAM1	endpt1	GA+GG	102	857	111	851	0.5198	0.92	0.7	1.198	0.0274	G	0.44	A	0.56
  hCV8726337	rs5498	ICAM1	endpt1	AA	31	430	53	365	0.0031	0.51	0.329	0.798	0.0274	G	0.44	A	0.56
  hCV8848630	rs7192	HLA-DRA	endpt1	TG+TT	74	802	106	737	0.0054	0.66	0.487	0.883	0.0756	T	0.38	G	0.62
  hCV8848630	rs7192	HLA-DRA	endpt1	GG	59	485	58	477	0.9870	1	0.698	1.441	0.0756	T	0.38	G	0.62
  hCV8851085	rs1042153	HLA-DPB1	endpt1	AG+AA	58	491	58	484	0.9498	0.99	0.687	1.422	0.0838	A	0.22	G	0.78
  hCV8851085	rs1042153	HLA-DPB1	endpt1	GG	74	798	106	731	0.0049	0.65	0.485	0.878	0.0838	A	0.22	G	0.78
  hCV8895373	rs1503185	PTPRJ	endpt1	AG+AA	53	409	44	394	0.5323	1.14	0.762	1.694	0.0203	A	0.18	G	0.82
  hCV8895373	rs1503185	PTPRJ	endpt1	GG	80	882	120	820	0.0018	0.64	0.481	0.847	0.0203	A	0.18	G	0.82
  hCV8901525	rs861539	KLC1	endpt1	AG+AA	88	759	86	734	0.9319	0.99	0.733	1.329	0.0204	A	0.37	G	0.63
  hCV8901525	rs861539	KLC1	endpt1	GG	45	504	75	457	0.0025	0.57	0.39	0.818	0.0204	A	0.37	G	0.63
  hCV8921288	rs1060621	GAPDH	endpt1	CA+CC	36	440	73	403	0.0003	0.48	0.319	0.71	0.0008	C	0.20	A	0.80
  hCV8921288	rs1060621	GAPDH	endpt1	AA	97	815	85	786	0.5588	1.09	0.815	1.459	0.0008	C	0.20	A	0.80
  hCV904973	rs7412	APOE	endpt1	TC+TT	19	141	11	135	0.2198	1.59	0.757	3.348	0.0416	T	0.06	C	0.94
  hCV904973	rs7412	APOE	endpt1	CC	114	1149	154	1081	0.0059	0.71	0.559	0.907	0.0416	T	0.06	C	0.94
  hCV9077561	rs1801274	FCGR2A	endpt1	GA+GG	96	985	133	891	0.0027	0.67	0.515	0.87	0.0357	G	0.50	A	0.50
  hCV9077561	rs1801274	FCGR2A	endpt1	AA	36	300	32	325	0.4605	1.2	0.743	1.926	0.0357	G	0.50	A	0.50
  hCV9494470			endpt1	TG+TT	33	407	54	365	0.0102	0.57	0.368	0.874	0.0957	T	0.17	G	0.83
  hCV9494470			endpt1	GG	100	884	111	851	0.3255	0.87	0.666	1.144	0.0957	T	0.17	G	0.83
  hCV9506149	rs1250259	FN1	endpt1	TA+TT	69	611	68	582	0.8631	0.97	0.695	1.357	0.0654	T	0.28	A	0.72
  hCV9506149	rs1250259	FN1	endpt1	AA	64	678	97	634	0.0042	0.63	0.46	0.865	0.0654	T	0.28	A	0.72
  hCV9604851	rs1805002	CCKBR	endpt1	AG+AA	19	113	14	140	0.1884	1.59	0.797	3.171	0.0273	A	0.05	G	0.95
  hCV9604851	rs1805002	CCKBR	endpt1	GG	114	1178	151	1075	0.0046	0.7	0.552	0.898	0.0273	A	0.05	G	0.95
  hCV2553030	rs11230562	CD6	endpt1	TC+CC	129	1179	154	1151	0.1178	0.83	0.657	1.048	0.0059	T	0.25	C	0.75
  hCV2553030	rs11230562	CD6	endpt1	TT	3	107	11	63	0.0062	0.17	0.047	0.603	0.0059	T	0.25	C	0.75
  hCV25637309	rs3204849	CCRL2	endpt1	AT+TT	109	1107	150	994	0.0013	0.67	0.522	0.855	0.0031	A	0.39	T	0.61
  hCV25637309	rs3204849	CCRL2	endpt1	AA	24	184	15	219	0.0572	1.87	0.981	3.566	0.0031	A	0.39	T	0.61
  hCV25640504			endpt1	TC+CC	113	1035	128	977	0.1795	0.84	0.653	1.083	0.0390	T	0.28	C	0.72
  hCV25640504			endpt1	TT	12	194	28	175	0.0084	0.4	0.205	0.792	0.0390	T	0.28	C	0.72
  hCV2769554	rs1805010	IL4R	endpt1	GA+AA	101	1001	144	939	0.0021	0.67	0.52	0.865	0.0118	G	0.46	A	0.54
  hCV2769554	rs1805010	IL4R	endpt1	GG	32	287	21	274	0.1841	1.45	0.837	2.518	0.0118	G	0.46	A	0.54
  hCV2822674	rs1801222	CUBN	endpt1	AG+GG	123	1140	144	1097	0.1375	0.83	0.655	1.06	0.0448	A	0.32	G	0.68
  hCV2822674	rs1801222	CUBN	endpt1	AA	10	150	21	117	0.0120	0.38	0.179	0.808	0.0448	A	0.32	G	0.68
  hCV2992252	rs6037651	SIGLEC1	endpt1	CT+TT	124	1089	140	1019	0.1532	0.84	0.658	1.068	0.0173	C	0.40	T	0.60
  hCV2992252	rs6037651	SIGLEC1	endpt1	CC	8	196	25	193	0.0052	0.32	0.145	0.713	0.0173	C	0.40	T	0.60
  hCV3187716	rs5186	AGTR1	endpt1	CA+AA	128	1176	143	1093	0.1486	0.84	0.661	1.065	0.0111	C	0.30	A	0.70
  hCV3187716	rs5186	AGTR1	endpt1	CC	5	112	22	118	0.0061	0.26	0.097	0.679	0.0111	C	0.30	A	0.70
  hCV3215409	rs267561	ITGA9	endpt1	GA+AA	118	1057	128	994	0.2979	0.88	0.682	1.124	0.0133	G	0.42	A	0.58
  hCV3215409	rs267561	ITGA9	endpt1	GG	15	235	37	222	0.0026	0.4	0.218	0.723	0.0133	G	0.42	A	0.58
  hCV3219460	rs1799983	NOS3	endpt1	TG+GG	124	1114	144	1065	0.1316	0.83	0.654	1.057	0.0495	T	0.35	G	0.65
  hCV3219460	rs1799983	NOS3	endpt1	TT	9	177	21	149	0.0157	0.38	0.175	0.834	0.0495	T	0.35	G	0.65
  hCV370782	rs9841174	SERPINI2	endpt1	CT+TT	113	1097	150	1022	0.0065	0.71	0.558	0.91	0.0938	C	0.38	T	0.62
  hCV370782	rs9841174	SERPINI2	endpt1	CC	20	194	15	189	0.4473	1.3	0.664	2.532	0.0938	C	0.38	T	0.62
  hCV7514870	rs1041981	LTA	endpt1	AC+CC	121	1118	144	1094	0.1397	0.83	0.655	1.061	0.0624	A	0.33	C	0.67
  hCV7514870	rs1041981	LTA	endpt1	AA	12	172	21	122	0.0110	0.4	0.194	0.809	0.0624	A	0.33	C	0.67
  hCV818008	rs5918	ITGB3	endpt1	CT+TT	126	1266	164	1194	0.0099	0.74	0.584	0.929	0.0236	C	0.15	T	0.85
  hCV818008	rs5918	ITGB3	endpt1	CC	7	26	1	22	0.1271	5.11	0.628	41.557	0.0236	C	0.15	T	0.85
  hCV8708473	rs1800469	TMEM91	endpt1	AG+GG	124	1153	145	1090	0.1014	0.82	0.644	1.04	0.0991	A	0.32	G	0.68
  hCV8708473	rs1800469	TMEM91	endpt1	AA	9	139	20	125	0.0331	0.43	0.193	0.934	0.0991	A	0.32	G	0.68
  hCV8709053	rs4880	SOD2	endpt1	GA+AA	105	954	117	928	0.3282	0.88	0.674	1.141	0.0636	G	0.50	A	0.50
  hCV8709053	rs4880	SOD2	endpt1	GG	28	335	47	285	0.0077	0.53	0.331	0.845	0.0636	G	0.50	A	0.50
  hCV8737990	rs419598	IL1RN	endpt1	CT+TT	117	1193	157	1104	0.0035	0.7	0.551	0.89	0.0157	C	0.28	T	0.72
  hCV8737990	rs419598	IL1RN	endpt1	CC	15	96	8	103	0.1156	1.99	0.844	4.699	0.0157	C	0.28	T	0.72
  hCV8784787	rs688976		endpt1	AC+CC	126	1234	163	1147	0.0088	0.73	0.581	0.925	0.0443	A	0.23	C	0.77
  hCV8784787	rs688976		endpt1	AA	6	57	2	69	0.1452	3.29	0.663	16.304	0.0443	A	0.23	C	0.77
  hCV8804621	rs1390938	SLC18A1	endpt1	AG+GG	125	1218	160	1132	0.0120	0.74	0.586	0.936	0.0805	A	0.25	G	0.75
  hCV8804621	rs1390938	SLC18A1	endpt1	AA	8	69	4	80	0.2298	2.09	0.628	6.934	0.0805	A	0.25	G	0.75
  hCV8851047	rs45614833	HLA-DPA1	endpt1	CT+TT	126	1229	158	1152	0.0224	0.76	0.602	0.962	0.0104	C	0.17	T	0.83
  hCV8851047	rs45614833	HLA-DPA1	endpt1	CC	7	32	1	37	0.0779	6.59	0.81	53.622	0.0104	C	0.17	T	0.83
  hCV8851065	rs9277343	HLA-DPA1	endpt1	GC+CC	120	1198	158	1120	0.0072	0.72	0.57	0.916	0.0322	G	0.28	C	0.72
  hCV8851065	rs9277343	HLA-DPA1	endpt1	GG	13	90	7	98	0.1152	2.1	0.835	5.264	0.0322	G	0.28	C	0.72
  hCV8851095	rs1042335	HLA-DPB1	endpt1	TC+CC	126	1216	157	1139	0.0229	0.76	0.603	0.963	0.0840	T	0.27	C	0.73
  hCV8851095	rs1042335	HLA-DPB1	endpt1	TT	7	40	4	50	0.1712	2.37	0.688	8.198	0.0840	T	0.27	C	0.73
  hCV9055799	rs3734311	IMPG1	endpt1	CG+GG	117	1040	142	1049	0.1628	0.84	0.658	1.073	0.0749	C	0.40	G	0.60
  hCV9055799	rs3734311	IMPG1	endpt1	CC	15	247	23	166	0.0153	0.45	0.233	0.857	0.0749	C	0.40	G	0.60
  hCV9596963	rs6115	SERPINA5	endpt1	GA+AA	106	1147	151	1098	0.0027	0.68	0.534	0.877	0.0181	G	0.32	A	0.68
  hCV9596963	rs6115	SERPINA5	endpt1	GG	26	136	14	117	0.1985	1.53	0.8	2.934	0.0181	G	0.32	A	0.68
  hCV997884	rs512770		endpt1	AG+GG	126	1241	162	1143	0.0079	0.73	0.578	0.921	0.0466	A	0.20	G	0.80
  hCV997884	rs512770		endpt1	AA	5	42	2	63	0.1428	3.41	0.661	17.577	0.0466	A	0.20	G	0.80
  hCV2983036	rs9527025	KL	endpt1	CC	4	22	2	27	0.3494	2.25	0.412	12.278	0.0793	C	0.15	G	0.85
  hCV2983036	rs9527025	KL	endpt1	CG	32	363	51	293	0.0043	0.53	0.338	0.818	0.0793	C	0.15	G	0.85
  hCV2983036	rs9527025	KL	endpt1	GG	97	906	112	891	0.2806	0.86	0.656	1.13	0.0793	C	0.15	G	0.85
  hCV3135085	rs10795446	CUBN	endpt1	GG	10	147	21	145	0.0690	0.5	0.234	1.056	0.0932	G	0.33	T	0.67
  hCV3135085	rs10795446	CUBN	endpt1	GT	64	554	61	532	0.9477	1.01	0.712	1.437	0.0932	G	0.33	T	0.67
  hCV3135085	rs10795446	CUBN	endpt1	TT	57	575	82	529	0.0116	0.65	0.462	0.908	0.0932	G	0.33	T	0.67
  hCV3275199	rs2069885	IL9	endpt1	AA	5	28	2	21	0.5551	1.64	0.318	8.446	0.0775	A	0.13	G	0.87
  hCV3275199	rs2069885	IL9	endpt1	AG	18	310	35	257	0.0060	0.45	0.255	0.796	0.0775	A	0.13	G	0.87
  hCV3275199	rs2069885	IL9	endpt1	GG	109	947	128	937	0.2088	0.85	0.658	1.096	0.0775	A	0.13	G	0.87
  hCV342590	rs6030	F5	endpt1	CC	15	123	13	130	0.6256	1.2	0.572	2.529	0.0995	C	0.31	T	0.69
  hCV342590	rs6030	F5	endpt1	CT	44	553	74	519	0.0034	0.57	0.394	0.832	0.0995	C	0.31	T	0.69
  hCV342590	rs6030	F5	endpt1	TT	74	613	78	566	0.4490	0.88	0.643	1.216	0.0995	C	0.31	T	0.69
  hCV435368	rs2812	PECAM1	endpt1	TT	40	272	44	270	0.6056	0.89	0.582	1.371	0.0948	T	0.47	C	0.53
  hCV435368	rs2812	PECAM1	endpt1	TC	56	649	86	573	0.0028	0.6	0.428	0.838	0.0948	T	0.47	C	0.53
  hCV435368	rs2812	PECAM1	endpt1	CC	37	369	34	373	0.7363	1.08	0.68	1.726	0.0948	T	0.47	C	0.53
  hCV11170747	rs2066853	AHR	endpt1	GG	112	1008	128	982	0.2728	0.87	0.673	1.118	0.0356	A	0.11	G	0.89
  hCV11170747	rs2066853	AHR	endpt1	AG+AA	20	283	36	235	0.0036	0.44	0.256	0.767	0.0356	A	0.11	G	0.89
  hCV11181829	rs5713	ACSM3	endpt1	TT	124	1259	161	1189	0.0112	0.74	0.584	0.933	0.0735	C	0.01	T	0.99
  hCV11181829	rs5713	ACSM3	endpt1	CT+CC	8	23	4	26	0.2129	2.14	0.646	7.125	0.0735	C	0.01	T	0.99
  hCV11225994	rs1853021	LPA	endpt1	GG	92	973	130	894	0.0026	0.66	0.508	0.866	0.0671	A	0.13	G	0.87
  hCV11225994	rs1853021	LPA	endpt1	AG+AA	37	311	34	314	0.7086	1.09	0.686	1.741	0.0671	A	0.13	G	0.87
  hCV11438723	rs 1877273	WWOX	endpt1	TT	0	12	3	13	0.9973	0	0	.	0.0772	T	0.10	C	0.90
  hCV11438723	rs 1877273	WWOX	endpt1	TC+CC	133	1270	162	1194	0.0368	0.78	0.623	0.985	0.0772	T	0.10	C	0.90
  hCV11461296		JAK3	endpt1	GG	125	1204	155	1153	0.0389	0.78	0.616	0.987	0.0111	C	0.02	G	0.98
  hCV11461296		JAK3	endpt1	CG+CC	1	49	9	36	0.0255	0.09	0.012	0.749	0.0111	C	0.02	G	0.98
  hCV11628130	rs2665802	GH1	endpt1	TT	18	254	33	212	0.0116	0.48	0.269	0.848	0.0640	T	0.42	A	0.58
  hCV11628130	rs2665802	GH1	endpt1	TA+AA	113	1034	130	1001	0.2005	0.85	0.659	1.091	0.0640	T	0.42	A	0.58
  hCV11642651	rs1800440	C2orf58	endpt1	CC	3	54	10	43	0.0467	0.27	0.074	0.981	0.0718	C	0.19	T	0.81
  hCV11642651	rs1800440	C2orf58	endpt1	CT+TT	130	1237	155	1171	0.0651	0.8	0.636	1.014	0.0718	C	0.19	T	0.81
  hCV11689916			endpt1	AA	35	369	56	340	0.0159	0.59	0.39	0.907	0.0899	A	0.48	T	0.52
  hCV11689916			endpt1	AT+TT	97	863	102	816	0.5024	0.91	0.689	1.201	0.0899	A	0.48	T	0.52
  hCV11697322	rs1926447	CPB2	endpt1	GG	59	655	93	616	0.0037	0.62	0.445	0.854	0.0540	A	0.29	G	0.71
  hCV11697322	rs1926447	CPB2	endpt1	AG+AA	74	632	72	600	0.8558	0.97	0.702	1.342	0.0540	A	0.29	G	0.71
  hCV11764545	rs4961	ADD1	endpt1	TT	2	52	7	41	0.0708	0.23	0.049	1.131	0.0921	T	0.18	G	0.82
  hCV11764545	rs4961	ADD1	endpt1	TG+GG	131	1238	158	1176	0.0573	0.8	0.634	1.007	0.0921	T	0.18	G	0.82
  hCV11955747	rs9901673	CD68	endpt1	CC	103	891	115	874	0.3731	0.89	0.679	1.156	0.0491	A	0.16	C	0.84
  hCV11955747	rs9901673	CD68	endpt1	AC+AA	30	399	50	341	0.0058	0.53	0.336	0.832	0.0491	A	0.16	C	0.84
  hCV11972326	rs5988	F13A1	endpt1	GG	13	69	8	80	0.2560	1.67	0.69	4.03	0.0738	G	0.24	C	0.76
  hCV11972326	rs5988	F13A1	endpt1	GC+CC	120	1217	156	1133	0.0103	0.73	0.577	0.929	0.0738	G	0.24	C	0.76
  hCV12020339	rs4531	DBH	endpt1	GG	104	1095	145	1035	0.0043	0.69	0.538	0.891	0.0686	T	0.08	G	0.92
  hCV12020339	rs4531	DBH	endpt1	TG+TT	28	192	20	174	0.4707	1.24	0.696	2.193	0.0686	T	0.08	G	0.92
  hCV12108469		CYP4A11	endpt1	AA	2	60	10	56	0.0353	0.2	0.043	0.893	0.0439	A	0.21	G	0.79
  hCV12108469		CYP4A11	endpt1	AG+GG	128	1225	155	1148	0.0427	0.79	0.621	0.992	0.0439	A	0.21	G	0.79
  hCV1243283	rs1716	ITGAE	endpt1	AA	10	151	23	113	0.0037	0.33	0.158	0.7	0.0173	A	0.33	G	0.67
  hCV1243283	rs1716	ITGAE	endpt1	AG+GG	123	1138	142	1101	0.1788	0.85	0.666	1.079	0.0173	A	0.33	G	0.67
  hCV1253630	rs2071307	ELN	endpt1	GG	40	450	66	396	0.0030	0.55	0.373	0.818	0.0332	A	0.41	G	0.59
  hCV1253630	rs2071307	ELN	endpt1	AG+AA	92	839	96	813	0.6277	0.93	0.7	1.24	0.0332	A	0.41	G	0.59
  hCV1345898	rs2230804	CHUK	endpt1	CC	21	322	38	281	0.0134	0.51	0.299	0.869	0.0835	C	0.48	T	0.52
  hCV1345898	rs2230804	CHUK	endpt1	CT+TT	111	964	127	930	0.2025	0.85	0.657	1.093	0.0835	C	0.48	T	0.52
  hCV1361979	rs25683	ACAT2	endpt1	GG	36	434	61	384	0.0037	0.54	0.36	0.821	0.0443	A	0.43	G	0.57
  hCV1361979	rs25683	ACAT2	endpt1	AG+AA	97	851	104	820	0.4633	0.9	0.684	1.189	0.0443	A	0.43	G	0.57
  hCV1375141	rs1881420	ALK	endpt1	CC	10	69	6	61	0.4852	1.43	0.521	3.947	0.0936	C	0.21	T	0.79
  hCV1375141	rs1881420	ALK	endpt1	CT	33	421	60	399	0.0053	0.55	0.357	0.835	0.0936	C	0.21	T	0.79
  hCV1375141	rs1881420	ALK	endpt1	TT	90	799	99	757	0.3071	0.86	0.648	1.146	0.0936	C	0.21	T	0.79
  hCV1552894	rs434473	ALOX12	endpt1	GG	16	212	43	222	0.0028	0.42	0.234	0.739	0.0162	G	0.42	A	0.58
  hCV1552894	rs434473	ALOX12	endpt1	GA+AA	116	1073	122	990	0.3177	0.88	0.681	1.133	0.0162	G	0.42	A	0.58
  hCV1552900	rs1126667	ALOX12	endpt1	AA	16	212	43	223	0.0030	0.42	0.236	0.744	0.0159	A	0.42	G	0.58
  hCV1552900	rs1126667	ALOX12	endpt1	AG+GG	117	1076	122	991	0.3456	0.89	0.687	1.141	0.0159	A	0.42	G	0.58
  hCV15746640	rs41271951	CTSS	endpt1	AA	109	1096	150	1021	0.0032	0.69	0.539	0.883	0.0177	G	0.08	A	0.92
  hCV15746640	rs41271951	CTSS	endpt1	GA+GG	24	194	15	193	0.1717	1.57	0.823	2.99	0.0177	G	0.08	A	0.92
  hCV15758290	rs6716834	LRP2	endpt1	AA	58	635	87	563	0.0030	0.6	0.434	0.843	0.0441	G	0.30	A	0.70
  hCV15758290	rs6716834	LRP2	endpt1	GA+GG	75	648	78	646	0.8294	0.97	0.703	1.326	0.0441	G	0.30	A	0.70
  hCV15760070	rs2308911	HLA-DPA1	endpt1	TT	7	31	1	38	0.0713	6.88	0.846	56.019	0.0073	T	0.17	A	0.83
  hCV15760070	rs2308911	HLA-DPA1	endpt1	TA+AA	126	1258	164	1179	0.0090	0.73	0.582	0.926	0.0073	T	0.17	A	0.83
  hCV15851335	rs17610395	CPT1A	endpt1	CC	111	1123	147	1039	0.0073	0.71	0.558	0.913	0.0891	T	0.07	C	0.93
  hCV15851335	rs17610395	CPT1A	endpt1	TC+TT	21	164	17	176	0.4412	1.29	0.678	2.437	0.0891	T	0.07	C	0.93
  hCV15851779	rs2230009	WRN	endpt1	AA	0	6	2	4	0.9977	0	0	.	0.0624	A	0.06	G	0.94
  hCV15851779	rs2230009	WRN	endpt1	AG	20	132	14	129	0.3772	1.36	0.687	2.693	0.0624	A	0.06	G	0.94
  hCV15851779	rs2230009	WRN	endpt1	GG	113	1150	149	1082	0.0103	0.73	0.569	0.927	0.0624	A	0.06	G	0.94
  hCV15876011	rs2228541	SERPINA6	endpt1	GG	35	261	24	239	0.3001	1.32	0.783	2.212	0.0268	G	0.45	T	0.55
  hCV15876011	rs2228541	SERPINA6	endpt1	GT+TT	96	991	137	951	0.0048	0.69	0.529	0.892	0.0268	G	0.45	T	0.55
  hCV15954277	rs2236379	PRKCQ	endpt1	AA	13	103	3	92	0.0411	3.7	1.054	12.989	0.0042	A	0.26	G	0.74
  hCV15954277	rs2236379	PRKCQ	endpt1	AG+GG	120	1188	162	1126	0.0054	0.72	0.565	0.906	0.0042	A	0.26	G	0.74
  hCV15955388	rs2227376	F2RL3	endpt1	CC	132	1247	157	1173	0.0594	0.8	0.635	1.009	0.0435	T	0.02	C	0.98
  hCV15955388	rs2227376	F2RL3	endpt1	TC+TT	1	42	8	42	0.0629	0.14	0.017	1.112	0.0435	T	0.02	C	0.98
  hCV15963535	rs2228591	NCOA2	endpt1	CC	124	1155	142	1087	0.1293	0.83	0.652	1.056	0.0412	G	0.05	C	0.95
  hCV15963535	rs2228591	NCOA2	endpt1	GC+GG	8	132	23	130	0.0128	0.36	0.161	0.805	0.0412	G	0.05	C	0.95
  hCV1600754	rs17288671	CXCL9	endpt1	CC	34	396	51	324	0.0099	0.56	0.366	0.872	0.0869	T	0.46	C	0.54
  hCV1600754	rs17288671	CXCL9	endpt1	TC+TT	99	892	114	893	0.3365	0.88	0.669	1.147	0.0869	T	0.46	C	0.54
  hCV1603697	rs2229475	HSPG2	endpt1	CC	122	1141	142	1083	0.1196	0.83	0.648	1.051	0.0985	T	0.06	C	0.94
  hCV1603697	rs2229475	HSPG2	endpt1	TC+TT	11	148	23	132	0.0253	0.44	0.215	0.904	0.0985	T	0.06	C	0.94
  hCV16044337	rs2569491	KLK14	endpt1	AA	7	127	26	114	0.0012	0.25	0.11	0.582	0.0028	A	0.31	G	0.69
  hCV16044337	rs2569491	KLK14	endpt1	AG+GG	126	1157	138	1095	0.2664	0.87	0.685	1.11	0.0028	A	0.31	G	0.69
  hCV16047108	rs2244008	LAMA2	endpt1	AA	104	1148	145	1062	0.0025	0.68	0.527	0.872	0.0174	G	0.06	A	0.94
  hCV16047108	rs2244008	LAMA2	endpt1	GA+GG	28	140	20	151	0.2238	1.43	0.804	2.537	0.0174	G	0.06	A	0.94
  hCV16172339	rs2229489	HSPG2	endpt1	AA	121	1140	141	1081	0.1176	0.82	0.646	1.05	0.0974	T	0.06	A	0.94
  hCV16172339	rs2229489	HSPG2	endpt1	TA+TT	11	147	23	131	0.0251	0.44	0.214	0.903	0.0974	T	0.06	A	0.94
  hCV16173091	rs2241883	FABP1	endpt1	CC	18	126	10	136	0.1086	1.88	0.869	4.079	0.0148	C	0.32	T	0.68
  hCV16173091	rs2241883	FABP1	endpt1	CT+TT	115	1164	155	1080	0.0041	0.7	0.552	0.894	0.0148	C	0.32	T	0.68
  hCV16179493	rs2108622	CYP4F2	endpt1	CC	54	613	90	574	0.0015	0.58	0.413	0.811	0.0241	T	0.31	C	0.69
  hCV16179493	rs2108622	CYP4F2	endpt1	TC+TT	77	670	75	640	0.9145	0.98	0.715	1.351	0.0241	T	0.31	C	0.69
  hCV16179628	rs2273697	ABCC2	endpt1	AA	1	68	4	28	0.0562	0.12	0.013	1.058	0.0472	A	0.20	G	0.80
  hCV16179628	rs2273697	ABCC2	endpt1	AG+GG	132	1220	161	1189	0.0668	0.81	0.641	1.015	0.0472	A	0.20	G	0.80
  hCV16182835	rs2274736	PTPN21	endpt1	AA	70	555	62	511	0.8609	1.03	0.733	1.451	0.0411	G	0.34	A	0.66
  hCV16182835	rs2274736	PTPN21	endpt1	GA+GG	62	703	98	684	0.0053	0.64	0.463	0.874	0.0411	G	0.34	A	0.66
  hCV16192174	rs2305948	KDR	endpt1	GG	96	1043	134	984	0.0052	0.69	0.53	0.895	0.0847	A	0.10	G	0.90
  hCV16192174	rs2305948	KDR	endpt1	AG+AA	37	248	31	232	0.6835	1.1	0.685	1.78	0.0847	A	0.10	G	0.90
  hCV1647371	rs3025000	VEGFA	endpt1	CC	57	600	88	529	0.0026	0.6	0.429	0.835	0.0251	T	0.33	C	0.67
  hCV1647371	rs3025000	VEGFA	endpt1	TC+TT	75	662	73	664	0.9194	1.02	0.737	1.403	0.0251	T	0.33	C	0.67
  hCV1741111	rs1764391	C1orf212	endpt1	TT	12	114	6	97	0.2976	1.68	0.632	4.486	0.0931	T	0.30	C	0.70
  hCV1741111	rs1764391	C1orf212	endpt1	TC+CC	121	1174	159	1118	0.0109	0.74	0.581	0.932	0.0931	T	0.30	C	0.70
  hCV1770462	rs12731981	MPL	endpt1	GG	114	1204	153	1141	0.0070	0.72	0.562	0.913	0.0818	A	0.03	G	0.97
  hCV1770462	rs12731981	MPL	endpt1	AG+AA	18	82	12	76	0.3614	1.41	0.677	2.918	0.0818	A	0.03	G	0.97
  hCV1843175	rs3745535	KLK10	endpt1	CC	57	528	59	538	0.9494	0.99	0.687	1.422	0.0787	A	0.36	C	0.64
  hCV1843175	rs3745535	KLK10	endpt1	AC+AA	75	754	106	675	0.0040	0.65	0.482	0.87	0.0787	A	0.36	C	0.64
  hCV2038	rs4673	CYBA	endpt1	GG	44	563	76	520	0.0018	0.55	0.382	0.803	0.0216	A	0.34	G	0.66
  hCV2038	rs4673	CYBA	endpt1	AG+AA	89	728	89	697	0.7717	0.96	0.714	1.284	0.0216	A	0.34	G	0.66
  hCV2143205	rs9666607	CD44	endpt1	AA	16	125	9	119	0.2301	1.65	0.729	3.732	0.0524	A	0.32	G	0.68
  hCV2143205	rs9666607	CD44	endpt1	AG+GG	117	1167	156	1099	0.0072	0.72	0.567	0.915	0.0524	A	0.32	G	0.68
  hCV22271999	rs2305948	KDR	endpt1	CC	96	1041	133	981	0.0060	0.69	0.532	0.9	0.0944	T	0.10	C	0.90
  hCV22271999	rs2305948	KDR	endpt1	TC+TT	37	248	31	230	0.7100	1.09	0.679	1.764	0.0944	T	0.10	C	0.90
  hCV22274761	rs11575194	IGFBP5	endpt1	GG	126	1175	149	1113	0.0831	0.81	0.64	1.028	0.0849	A	0.04	G	0.96
  hCV22274761	rs11575194	IGFBP5	endpt1	AG+AA	6	108	16	100	0.0333	0.36	0.141	0.923	0.0849	A	0.04	G	0.96
  hCV22275550	rs6836335	SPON2	endpt1	CC	3	15	1	28	0.2235	4.08	0.424	39.314	0.0946	C	0.12	T	0.88
  hCV22275550	rs6836335	SPON2	endpt1	CT+TT	129	1270	164	1189	0.0139	0.75	0.594	0.943	0.0946	C	0.12	T	0.88
  hCV2230606	rs13268	FBLN1	endpt1	AA	124	1224	161	1153	0.0109	0.74	0.584	0.932	0.0281	G	0.02	A	0.98
  hCV2230606	rs13268	FBLN1	endpt1	GA+GG	9	62	3	63	0.1073	2.93	0.792	10.814	0.0281	G	0.02	A	0.98
  hCV2276802	rs381418	GBA	endpt1	AA	33	354	54	313	0.0088	0.56	0.364	0.865	0.0820	C	0.37	A	0.63
  hCV2276802	rs381418	GBA	endpt1	CA+CC	100	935	110	903	0.3623	0.88	0.673	1.156	0.0820	C	0.37	A	0.63
  hCV2310409	45474794-rs6.	APOA4	endpt1	TT	76	825	107	756	0.0061	0.66	0.494	0.889	0.1000	A	0.20	T	0.80
  hCV2310409	45474794-rs6.	APOA4	endpt1	AT+AA	56	459	56	450	0.9347	0.98	0.68	1.426	0.1000	A	0.20	T	0.80
  hCV2485037	rs4904448	SPATA7	endpt1	AA	31	228	23	219	0.4154	1.25	0.73	2.146	0.0581	A	0.43	G	0.57
  hCV2485037	rs4904448	SPATA7	endpt1	AG+GG	101	1032	137	985	0.0082	0.71	0.547	0.914	0.0581	A	0.43	G	0.57
  hCV2503034	rs1132356	BAIAP3	endpt1	AA	0	16	3	4	0.9978	0	0	.	0.0411	A	0.11	C	0.89
  hCV2503034	rs1132356	BAIAP3	endpt1	AC	34	258	35	219	0.3764	0.81	0.504	1.296	0.0411	A	0.11	C	0.89
  hCV2503034	rs1132356	BAIAP3	endpt1	CC	97	1010	126	985	0.0498	0.77	0.589	1	0.0411	A	0.11	C	0.89
  hCV2531086	rs10406069	CD22	endpt1	AA	7	52	2	47	0.1378	3.29	0.682	15.892	0.0460	A	0.21	G	0.79
  hCV2531086	rs10406069	CD22	endpt1	AG+GG	124	1236	163	1167	0.0081	0.73	0.577	0.921	0.0460	A	0.21	G	0.79
  hCV2536595	rs704	VTN	endpt1	GG	44	351	34	381	0.1617	1.38	0.88	2.154	0.0027	A	0.47	G	0.53
  hCV2536595	rs704	VTN	endpt1	AG+AA	89	940	131	837	0.0005	0.62	0.475	0.814	0.0027	A	0.47	G	0.53
  hCV25472345	rs4900072	C14orf159	endpt1	TT	8	154	29	160	0.0036	0.31	0.143	0.683	0.0075	T	0.34	C	0.66
  hCV25472345	rs4900072	C14orf159	endpt1	TC+CC	124	1108	130	1029	0.3416	0.89	0.694	1.135	0.0075	T	0.34	C	0.66
  hCV25472673	rs1805081	NPC1	endpt1	TT	59	484	47	455	0.4153	1.17	0.799	1.72	0.0080	C	0.39	T	0.61
  hCV25472673	rs1805081	NPC1	endpt1	CT+CC	74	803	117	761	0.0010	0.61	0.459	0.822	0.0080	C	0.39	T	0.61
  hCV25473098	rs2241883	FABP1	endpt1	GG	18	124	11	137	0.1440	1.75	0.826	3.704	0.0227	G	0.31	A	0.69
  hCV25473098	rs2241883	FABP1	endpt1	GA+AA	115	1165	152	1071	0.0055	0.71	0.557	0.904	0.0227	G	0.31	A	0.69
  hCV25474101	rs41554412	MICA	endpt1	CC	7	25	2	32	0.0951	3.81	0.792	18.358	0.0195	C	0.15	T	0.85
  hCV25474101	rs41554412	MICA	endpt1	CT+TT	126	1266	163	1184	0.0094	0.73	0.582	0.927	0.0195	C	0.15	T	0.85
  hCV25591528		CD163	endpt1	GG	114	994	128	956	0.2637	0.87	0.673	1.115	0.0417	A	0.12	G	0.88
  hCV25591528		CD163	endpt1	AG+AA	19	296	37	262	0.0065	0.46	0.267	0.807	0.0417	A	0.12	G	0.88
  hCV25596880	rs4647297	CASP2	endpt1	CC	2	3	0	6	0.9977	1E+08	0	.	0.0713	C	0.06	G	0.94
  hCV25596880	rs4647297	CASP2	endpt1	CG	12	136	12	137	0.9890	0.99	0.447	2.214	0.0713	C	0.06	G	0.94
  hCV25596880	rs4647297	CASP2	endpt1	GG	118	1150	153	1072	0.0107	0.73	0.575	0.93	0.0713	C	0.06	G	0.94
  hCV25598594	rs41274768	CR1	endpt1	GG	132	1226	154	1167	0.1016	0.82	0.653	1.039	0.0028	A	0.02	G	0.98
  hCV25598594	rs41274768	CR1	endpt1	AG+AA	1	65	11	50	0.0150	0.08	0.01	0.61	0.0028	A	0.02	G	0.98
  hCV25603879	rs11542844	SCNN1A	endpt1	CC	122	1200	160	1126	0.0082	0.73	0.575	0.921	0.0527	T	0.03	C	0.97
  hCV25603879	rs11542844	SCNN1A	endpt1	TC+TT	11	89	5	85	0.2080	1.97	0.685	5.68	0.0527	T	0.03	C	0.97
  hCV25605897	rs11568563	SLCO1A2	endpt1	TT	126	1140	144	1088	0.1708	0.85	0.666	1.075	0.0166	G	0.06	T	0.94
  hCV25605897	rs11568563	SLCO1A2	endpt1	GT+GG	7	150	20	126	0.0065	0.3	0.128	0.716	0.0166	G	0.06	T	0.94
  hCV25607193		FLNB	endpt1	TT	127	1258	164	1191	0.0129	0.75	0.591	0.94	0.0477	C	0.01	T	0.99
  hCV25607193		FLNB	endpt1	CT+CC	6	33	1	27	0.1685	4.42	0.533	36.753	0.0477	C	0.01	T	0.99
  hCV25608818		SLC10A2	endpt1	GG	126	1258	162	1176	0.0110	0.74	0.586	0.933	0.0206	A	0.01	G	0.99
  hCV25608818		SLC10A2	endpt1	AG+AA	7	32	2	40	0.0832	4.01	0.833	19.312	0.0206	A	0.01	G	0.99
  hCV25610470	rs34075341	C9orf47	endpt1	GG	128	1182	151	1128	0.0946	0.82	0.646	1.0365	0.0431	A	0.04	G	0.96
  hCV25610470	rs34075341	C9orf47	endpt1	AG+AA	4	103	13	87	0.0235	0.27	0.089	0.84	0.0431	A	0.04	G	0.96
  hCV25610774	rs8176748		endpt1	TT	5	57	2	67	0.2456	2.64	0.512	13.644	0.0989	T	0.23	C	0.77
  hCV25610774	rs8176748		endpt1	TC+CC	127	1231	163	1150	0.0116	0.74	0.588	0.935	0.0989	T	0.23	C	0.77
  hCV25610819	rs8176740		endpt1	TT	5	58	2	70	0.2297	2.73	0.53	14.102	0.0925	T	0.23	A	0.77
  hCV25610819	rs8176740		endpt1	TA+AA	128	1225	163	1139	0.0122	0.74	0.59	0.937	0.0925	T	0.23	A	0.77
  hCV25614016	rs7607759	CAPN10	endpt1	AA	87	915	130	840	0.0010	0.63	0.482	0.83	0.0072	G	0.16	A	0.84
  hCV25614016	rs7607759	CAPN10	endpt1	GA+GG	46	374	35	374	0.2727	1.28	0.824	1.985	0.0075	G	0.16	A	0.84
  hCV25617571	rs2232580	LBP	endpt1	CC	117	1090	132	1052	0.2572	0.87	0.675	1.111	0.0208	T	0.08	C	0.92
  hCV25617571	rs2232580	LBP	endpt1	TC+TT	16	200	33	165	0.0037	0.41	0.227	0.751	0.0208	T	0.08	C	0.92
  hCV25623265	rs3746638	SIGLEC1	endpt1	GG	14	288	40	279	0.0008	0.35	0.193	0.65	0.0039	G	0.48	A	0.52
  hCV25623265	rs3746638	SIGLEC1	endpt1	GA+AA	118	1000	125	936	0.3626	0.89	0.692	1.144	0.0039	G	0.48	A	0.52
  hCV25629396	rs3729823	MYH7	endpt1	GG	125	1260	163	1166	0.0064	0.72	0.573	0.913	0.0011	C	0.01	G	0.99
  hCV25629396	rs3729823	MYH7	endpt1	CG+CC	7	26	1	48	0.0266	10.7	1.317	87.094	0.0011	C	0.01	G	0.99
  hCV25629476	rs2427284	LAMA5	endpt1	GG	111	1158	150	1095	0.0071	0.71	0.558	0.912	0.0602	A	0.05	G	0.95
  hCV25629476	rs2427284	LAMA5	endpt1	AG+AA	22	131	14	121	0.3104	1.41	0.724	2.765	0.0602	A	0.05	G	0.95
  hCV25629492	rs944895	LAMA5	endpt1	AA	66	511	71	513	0.6944	0.94	0.669	1.307	0.0916	G	0.36	A	0.64
  hCV25629492	rs944895	LAMA5	endpt1	GA+GG	64	773	94	696	0.0043	0.63	0.458	0.865	0.0916	G	0.36	A	0.64
  hCV25629888	rs11539441	TIMP2	endpt1	GG	7	30	3	34	0.1786	2.53	0.654	9.788	0.0742	G	0.17	C	0.83
  hCV25629888	rs11539441	TIMP2	endpt1	GC+CC	125	1260	161	1184	0.0120	0.74	0.587	0.936	0.0742	G	0.17	C	0.83
  hCV25652744	rs1127525	USP21	endpt1	AA	1	0	0	4	1.000	4E+12	0	.	0.0261	A	0.05	C	0.95
  hCV25652744	rs1127525	USP21	endpt1	AC	5	113	15	107	0.0373	0.34	0.124	0.939	0.0261	A	0.05	C	0.95
  hCV25652744	rs1127525	USP21	endpt1	CC	127	1153	145	1082	0.1210	0.83	0.653	1.051	0.0261	A	0.05	C	0.95
  hCV1026586	rs673548	APOB	endpt1	GA+GG	127	1203	163	1147	0.0160	0.75	0.60	0.95	0.0780	A	0.22	G	0.78
  hCV1026586	rs673548	APOB	endpt1	AA	9	59	4	58	0.2000	2.15	0.66	6.97	0.0780	A	0.22	G	0.78
  hCV11466848	rs1805419	BAX	endpt1	AG+AA	53	620	93	563	0.0003	0.54	0.38	0.75	0.0020	A	0.28	G	0.72
  hCV11466848	rs1805419	BAX	endpt1	GG	83	645	74	643	0.5200	1.11	0.81	1.52	0.0020	A	0.28	G	0.72
  hCV11513719	rs2967605	ELAVL1	endpt1	TC+TT	40	425	67	372	0.0019	0.54	0.36	0.80	0.0180	C	0.82	T	0.18
  hCV11513719	rs2967605	ELAVL1	endpt1	CC	95	832	99	829	0.7800	0.96	0.73	1.27	0.0180	C	0.82	T	0.18
  hCV1323634	rs287475		endpt1	TC+TT	106	1034	149	980	0.0031	0.69	0.54	0.88	0.0074	C	0.43	T	0.57
  hCV1323634	rs287475		endpt1	CC	30	229	18	225	0.1000	1.63	0.91	2.93	0.0074	C	0.43	T	0.57
  hCV1323669	rs287354		endpt1	GA+GG	104	1023	144	968	0.0048	0.70	0.54	0.89	0.0190	A	0.44	G	0.56
  hCV1323669	rs287354		endpt1	AA	32	244	22	239	0.2100	1.42	0.82	2.44	0.0190	A	0.44	G	0.56
  hCV1729928	rs10509384	KCNMA1	endpt1	AG+AA	117	1119	153	1043	0.0096	0.73	0.57	0.93	0.0880	A	0.66	G	0.34
  hCV1729928	rs10509384	KCNMA1	endpt1	GG	18	142	14	158	0.3600	1.39	0.69	2.79	0.0880	A	0.66	G	0.34
  hCV1948599	rs504527	CSMD2	endpt1	CA+CC	92	989	129	920	0.0041	0.68	0.52	0.88	0.0320	A	0.49	C	0.51
  hCV1948599	rs504527	CSMD2	endpt1	AA	44	275	38	283	0.4600	1.18	0.76	1.82	0.0320	A	0.49	C	0.51
  hCV2554615	rs2522057	LOC441108	endpt1	CG+CC	107	1046	146	998	0.0098	0.72	0.56	0.92	0.0580	C	0.58	G	0.42
  hCV2554615	rs2522057	LOC441108	endpt1	GG	29	216	20	208	0.3900	1.28	0.73	2.27	0.0580	C	0.58	G	0.42
  hCV2554721	rs7315519	RPH3A	endpt1	AG+AA	84	911	130	844	0.0005	0.62	0.47	0.81	0.0015	A	0.46	G	0.54
  hCV2554721	rs7315519	RPH3A	endpt1	GG	52	355	37	361	0.1200	1.39	0.91	2.12	0.0015	A	0.46	G	0.54
  hCV260164	rs6754295		endpt1	TG+TT	127	1195	163	1138	0.0160	0.75	0.60	0.95	0.0720	G	0.24	T	0.76
  hCV260164	rs6754295		endpt1	GG	9	68	4	68	0.1900	2.19	0.67	7.10	0.0720	G	0.24	T	0.76
  hCV2762168	rs3939286		endpt1	TC+TT	62	592	91	531	0.0052	0.63	0.46	0.87	0.0600	C	0.74	T	0.26
  hCV2762168	rs3939286		endpt1	CC	74	673	76	673	0.8700	0.97	0.71	1.34	0.0600	C	0.74	T	0.26
  hCV2781953	rs6021931		endpt1	GT+GG	127	1214	161	1158	0.0220	0.76	0.6	0.96	0.0870	G	0.81	T	0.19
  hCV2781953	rs6021931		endpt1	TT	9	49	4	46	0.2000	2.15	0.66	7.02	0.0870	G	0.81	T	0.19
  hCV29011391	rs7557067		endpt1	AG+AA	126	1191	163	1139	0.0150	0.75	0.59	0.95	0.0790	A	0.76	G	0.24
  hCV29011391	rs7557067		endpt1	GG	9	69	4	67	0.2100	2.13	0.66	6.91	0.0790	A	0.76	G	0.24
  hCV29135108	rs6743779	KLF7	endpt1	CA+CC	61	661	103	633	0.0009	0.58	0.43	0.80	0.0076	A	0.69	C	0.31
  hCV29135108	rs6743779	KLF7	endpt1	AA	74	601	64	572	0.5900	1.10	0.78	1.53	0.0076	A	0.69	C	0.31
  hCV30264691	rs10508518	CUBN	endpt1	TG+TT	121	1148	157	1087	0.0140	0.75	0.59	0.94	0.0910	G	0.30	T	0.70
  hCV30264691	rs10508518	CUBN	endpt1	GG	15	111	10	116	0.3000	1.53	0.69	3.41	0.0910	G	0.30	T	0.70
  hCV30606396	rs10438978		endpt1	TC+TT	40	428	62	375	0.0074	0.58	0.39	0.86	0.0650	C	0.82	T	0.18
  hCV30606396	rs10438978		endpt1	CC	96	834	105	830	0.5400	0.92	0.70	1.21	0.0650	C	0.82	T	0.18
  hCV31237961	rs11950562	SLC22A4	endpt1	AC+AA	101	986	143	936	0.0046	0.69	0.54	0.89	0.0260	A	0.53	C	0.47
  hCV31237961	rs11950562	SLC22A4	endpt1	CC	35	279	24	268	0.3100	1.31	0.78	2.2	0.0260	A	0.53	C	0.47
  hCV3168675	rs469930		endpt1	GA+GG	77	766	109	709	0.0066	0.67	0.5	0.89	0.0790	A	0.64	G	0.36
  hCV3168675	rs469930		endpt1	AA	59	499	58	495	0.9500	1.01	0.7	1.45	0.0790	A	0.64	G	0.36
  hCV3170445	rs272893	SLC22A4	endpt1	TC+TT	81	779	121	732	0.0032	0.65	0.49	0.87	0.0260	C	0.61	T	0.39
  hCV3170445	rs272893	SLC22A4	endpt1	CC	55	487	46	474	0.5400	1.13	0.76	1.67	0.0260	C	0.61	T	0.39
  hCV3170459	rs1050152	SLC22A4	endpt1	CT+CC	105	1038	145	989	0.0079	0.71	0.55	0.91	0.0550	C	0.58	T	0.42
  hCV3170459	rs1050152	SLC22A4	endpt1	TT	31	223	22	217	0.4200	1.25	0.72	2.16	0.0550	C	0.58	T	0.42
  hCV3242919	rs486394		endpt1	AC+AA	120	1158	159	1110	0.0110	0.74	0.58	0.93	0.0490	A	0.71	C	0.29
  hCV3242919	rs486394		endpt1	CC	16	104	8	96	0.1800	1.78	0.76	4.17	0.0490	A	0.71	C	0.29
  hCV3242952	rs2000571		endpt1	AG+AA	42	464	74	448	0.0035	0.57	0.39	0.83	0.0320	A	0.21	G	0.79
  hCV3242952	rs2000571		endpt1	GG	94	799	93	757	0.7700	0.96	0.72	1.28	0.0320	A	0.21	G	0.79
  hCV610861	rs636887		endpt1	TC+TT	108	1017	146	973	0.0110	0.72	0.56	0.93	0.0900	C	0.43	T	0.57
  hCV610861	rs636887		endpt1	CC	28	247	21	233	0.4800	1.23	0.7	2.16	0.0900	C	0.43	T	0.57
  hCV7501549	rs1467412	ATP9A	endpt1	C+CC	93	947	132	903	0.0063	0.69	0.53	0.9	0.0620	C	0.50	T	0.50
  hCV7501549	rs1467412	ATP9A	endpt1	TT	43	319	35	303	0.5800	1.13	0.73	1.77	0.0620	C	0.50	T	0.50
  hCV7537517	rs1501908		endpt1	CG+CC	117	1087	156	1041	0.0100	0.73	0.58	0.93	0.0320	C	0.64	G	0.36
  hCV7537517	rs1501908		endpt1	GG	19	175	10	165	0.1500	1.75	0.82	3.77	0.0320	C	0.64	G	0.36
  hCV7910239	rs1541296	FVT1	endpt1	AG+AA	118	1111	152	1041	0.0140	0.74	0.58	0.94	0.0850	A	0.66	G	0.34
  hCV7910239	rs1541296	FVT1	endpt1	GG	18	147	14	163	0.3200	1.43	0.71	2.87	0.0850	A	0.66	G	0.34
  hCV8420416	rs719909	PANK1	endpt1	CT+CC	131	1236	165	1164	0.0200	0.76	0.61	0.96	0.0770	C	0.84	T	0.16
  hCV8420416	rs719909	PANK1	endpt1	TT	5	26	2	41	0.1500	3.29	0.64	16.97	0.0770	C	0.84	T	0.16
  hCV8785827	rs992969	IL33	endpt1	AG+AA	61	591	91	527	0.0038	0.62	0.45	0.86	0.0430	A	0.26	G	0.74
  hCV8785827	rs992969	IL33	endpt1	GG	75	675	76	677	0.9400	0.99	0.72	1.36	0.0430	A	0.26	G	0.74
  hCV8892418	rs901746	ACP2	endpt1	GA+GG	53	630	87	593	0.0024	0.59	0.42	0.83	0.0220	A	0.71	G	0.29
  hCV8892418	rs901746	ACP2	endpt1	AA	83	632	80	613	0.9600	1.01	0.74	1.37	0.0220	A	0.71	G	0.29
  hCV11678789	rs7219148		endpt1	TG+GG	111	918	116	905	0.6900	0.95	0.73	1.23	0.0058	G	0.48	T	0.52
  hCV11678789	rs7219148		endpt1	TT	25	348	51	301	0.0007	0.44	0.27	0.71	0.0058	G	0.48	T	0.52
  hCV11864162	rs1167998	DOCK7	endpt1	AC+CC	84	692	90	701	0.7400	0.95	0.71	1.28	0.0660	A	0.66	C	0.34
  hCV11864162	rs1167998	DOCK7	endpt1	AA	52	570	76	504	0.0074	0.62	0.43	0.88	0.0660	A	0.66	C	0.34
  hCV1239369	rs275982		endpt1	CA+AA	88	713	90	698	0.7300	0.95	0.71	1.27	0.0510	A	0.35	C	0.65
  hCV1239369	rs275982		endpt1	CC	48	552	77	508	0.0051	0.6	0.42	0.86	0.0510	A	0.35	C	0.65
  hCV1488444	rs10164405		endpt1	TG+GG	129	1159	148	1096	0.1400	0.84	0.66	1.06	0.0910	G	0.71	T	0.29
  hCV1488444	rs10164405		endpt1	TT	7	103	19	107	0.0240	0.37	0.15	0.88	0.0910	G	0.71	T	0.29
  hCV1489995	rs4013819	LOC392281	endpt1	GC+CC	120	1076	133	1035	0.2900	0.88	0.68	1.12	0.0440	C	0.63	G	0.37
  hCV1489995	rs4013819	LOC392281	endpt1	GG	16	185	34	170	0.0090	0.45	0.25	0.82	0.0440	C	0.63	G	0.37
  hCV15870728	rs2943245	C10orf64	endpt1	CT+TT	106	922	112	868	0.4000	0.89	0.68	1.16	0.0890	C	0.53	T	0.47
  hCV15870728	rs2943245	C10orf64	endpt1	CC	30	340	55	338	0.0130	0.57	0.36	0.89	0.0890	C	0.53	T	0.47
  hCV1802755	rs7764347	RFXDC1	endpt1	CT+TT	134	1216	158	1165	0.0920	0.82	0.65	1.03	0.0880	C	0.18	T	0.82
  hCV1802755	rs7764347	RFXDC1	endpt1	CC	2	47	9	40	0.0470	0.21	0.05	0.98	0.0880	C	0.18	T	0.82
  hCV2557331	rs233716	RPH3A	endpt1	CT+TT	118	1029	133	1001	0.2600	0.87	0.68	1.11	0.0830	C	0.42	T	0.58
  hCV2557331	rs233716	RPH3A	endpt1	CC	18	235	33	203	0.0190	0.5	0.28	0.89	0.0830	C	0.42	T	0.58
  hCV2632070	rs714052	BAZ1B	endpt1	AG+GG	40	289	30	263	0.4300	1.21	0.75	1.94	0.0400	A	0.88	G	0.12
  hCV2632070	rs714052	BAZ1B	endpt1	AA	96	974	137	940	0.0050	0.69	0.53	0.89	0.0400	A	0.88	G	0.12
  hCV2632498	rs3812316	MLXIPL	endpt1	CG+GG	40	297	33	277	0.6200	1.12	0.71	1.78	0.0780	C	0.87	G	0.13
  hCV2632498	rs3812316	MLXIPL	endpt1	CC	96	969	134	929	0.0076	0.7	0.54	0.91	0.0780	C	0.87	G	0.13
  hCV2632544	rs17145738		endpt1	CT+TT	41	283	31	271	0.3400	1.25	0.79	2.00	0.0230	C	0.88	T	0.12
  hCV2632544	rs17145738		endpt1	CC	95	983	136	936	0.0037	0.68	0.52	0.88	0.0230	C	0.88	T	0.12
  hCV28974083	rs8032553	C15orf42	endpt1	GA+AA	105	902	116	899	0.4500	0.90	0.69	1.18	0.0510	A	0.48	G	0.52
  hCV28974083	rs8032553	C15orf42	endpt1	GG	31	360	51	306	0.0067	0.54	0.35	0.84	0.0510	A	0.48	G	0.52
  hCV31145250	rs 10889353	DOCK7	endpt1	AC+CC	84	685	87	687	0.8600	0.97	0.72	1.31	0.0450	A	0.66	C	0.34
  hCV31145250	rs10889353	DOCK7	endpt1	AA	52	575	79	519	0.0053	0.61	0.43	0.86	0.0450	A	0.66	C	0.34
  hCV31528409	rs7635061		endpt1	AG+GG	74	606	74	587	0.8400	0.97	0.7	1.34	0.0850	A	0.71	G	0.29
  hCV31528409	rs7635061		endpt1	AA	62	659	92	619	0.0085	0.65	0.47	0.9	0.0850	A	0.71	G	0.29
  hCV31954792	rs6477693	C9orf4	endpt1	CA+AA	129	1163	148	1103	0.1400	0.84	0.66	1.06	0.0830	A	0.72	C	0.28
  hCV31954792	rs6477693	C9orf4	endpt1	CC	7	103	19	101	0.0280	0.38	0.16	0.9	0.0830	A	0.72	C	0.28
  hCV461035	rs7746448		endpt1	TC+CC	89	785	99	796	0.5300	0.91	0.69	1.21	0.0970	C	0.40	T	0.60
  hCV461035	rs7746448		endpt1	TT	47	481	68	410	0.0094	0.61	0.42	0.89	0.0970	C	0.40	T	0.60
  hCV601961	rs568654	ZNF568	endpt1	AG+GG	118	1072	135	1040	0.2200	0.86	0.67	1.10	0.0950	A	0.38	G	0.62
  hCV601961	rs568654	ZNF568	endpt1	AA	18	190	32	166	0.0210	0.51	0.28	0.90	0.0950	A	0.38	G	0.62
  hCV8785824	rs1412426		endpt1	AC+CC	128	1137	142	1080	0.2300	0.86	0.68	1.1	0.0200	A	0.33	C	0.67
  hCV8785824	rs1412426		endpt1	AA	8	127	25	122	0.0060	0.33	0.15	0.73	0.0200	A	0.33	C	0.67
  hCV9581635	rs1748195	DOCK7	endpt1	CG+GG	84	687	88	694	0.8500	0.97	0.72	1.31	0.0440	C	0.66	G	0.34
  hCV9581635	rs1748195	DOCK7	endpt1	CC	52	575	78	511	0.0051	0.61	0.43	0.86	0.0440	C	0.66	G	0.34
  hCV9588862	rs995000	DOCK7	endpt1	CT+TT	84	688	88	683	0.7600	0.95	0.71	1.29	0.0570	C	0.66	T	0.34
  hCV9588862	rs995000	DOCK7	endpt1	CC	52	577	79	523	0.0057	0.61	0.43	0.87	0.0570	C	0.66	T	0.34
  hDV76976592	rs4149274	ABCA1	endpt1	GA+AA	84	705	83	669	0.8100	0.96	0.71	1.31	0.0540	A	0.34	G	0.66
  hDV76976592	rs4149274	ABCA1	endpt1	GG	52	557	84	537	0.0057	0.61	0.43	0.87	0.0540	A	0.34	G	0.66
  hCV11568668	rs1317538	KCNQ5	endpt1	AA	43	324	49	277	0.2300	0.78	0.52	1.17	0.0343	A	0.49	G	0.51
  hCV11568668	rs1317538	KCNQ5	endpt1	AG	70	607	67	603	0.9100	1.02	0.73	1.43	0.0343	A	0.49	G	0.51
  hCV11568668	rs1317538	KCNQ5	endpt1	GG	23	336	50	328	0.0028	0.47	0.29	0.77	0.0343	A	0.49	G	0.51
  hCV2221541	rs739161		endpt1	CC	7	121	17	80	0.0066	0.30	0.12	0.71	0.0367	C	0.29	T	0.71
  hCV2221541	rs739161		endpt1	TC	55	492	60	535	0.9400	0.99	0.68	1.42	0.0367	C	0.29	T	0.71
  hCV2221541	rs739161		endpt1	TT	74	649	90	591	0.0910	0.77	0.56	1.04	0.0367	C	0.29	T	0.71
  hCV601962	rs544543	ZNF568	endpt1	AA	44	522	66	457	0.0088	0.60	0.41	0.88	0.0198	A	0.62	G	0.38
  hCV601962	rs544543	ZNF568	endpt1	GA	71	545	69	579	0.6100	1.09	0.78	1.52	0.0198	A	0.62	G	0.38
  hCV601962	rs544543	ZNF568	endpt1	GG	18	191	32	168	0.0240	0.51	0.29	0.92	0.0198	A	0.62	G	0.38
  hCV8369472	rs1447351	MTNR1B	endpt1	GG	42	347	59	322	0.0610	0.68	0.46	1.02	0.0471	A	0.48	G	0.52
  hCV8369472	rs1447351	MTNR1B	endpt1	GA	65	586	65	632	0.7100	1.07	0.76	1.50	0.0471	A	0.48	G	0.52
  hCV8369472	rs1447351	MTNR1B	endpt1	AA	29	330	43	252	0.0088	0.53	0.33	0.85	0.0471	A	0.48	G	0.52
  hCV22303	rs4552916		endpt1	AA	86	788	95	755	0.3600	0.87	0.65	1.17	0.0391	A	0.78	G	0.22
  hCV22303	rs4552916		endpt1	GA	37	408	65	383	0.0038	0.55	0.37	0.82	0.0391	A	0.78	G	0.22
  hCV22303	rs4552916		endpt1	GG	13	70	7	68	0.2400	1.73	0.69	4.33	0.0391	A	0.78	G	0.22
  hCV601946	rs524802	ZNF568	endpt1	AA	17	175	29	156	0.0410	0.54	0.29	0.97	0.0203	A	0.37	G	0.63
  hCV601946	rs524802	ZNF568	endpt1	AG	74	554	70	578	0.5700	1.1	0.79	1.53	0.0203	A	0.37	G	0.63
  hCV601946	rs524802	ZNF568	endpt1	GG	45	536	68	471	0.0077	0.6	0.41	0.87	0.0203	A	0.37	G	0.63
  hCV922535	rs748065		endpt1	AA	74	611	76	587	0.7300	0.95	0.69	1.3	0.0842	A	0.70	G	0.30
  hCV922535	rs748065		endpt1	GA	48	541	81	520	0.0032	0.58	0.41	0.84	0.0842	A	0.70	G	0.30
  hCV922535	rs748065		endpt1	GG	14	114	10	98	0.7000	1.17	0.52	2.63	0.0842	A	0.70	G	0.30
  hDV70797856	rs17006217		endpt1	CC	2	14	0	13	1.0000	1E+09	0	Inf	0.0397	C	0.11	T	0.89
  hDV70797856	rs17006217		endpt1	CT	25	255	45	231	0.0084	0.52	0.32	0.84	0.0397	C	0.11	T	0.89
  hDV70797856	rs17006217		endpt1	TT	109	997	122	962	0.3000	0.87	0.67	1.13	0.0397	C	0.11	T	0.89
  hCV11856381	rs2197089		rmi	AG+AA	84	1006	129	970	0.0018	0.65	0.49	0.85	0.0420	A	0.54	G	0.46
  hCV11856381	rs2197089		rmi	GG	27	279	19	253	0.4300	1.26	0.70	2.27	0.0420	A	0.54	G	0.46
  hCV16140621	rs2156552		rmi	AT+AA	30	416	53	371	0.0045	0.52	0.33	0.82	0.0810	A	0.17	T	0.83
  hCV16140621	rs2156552		rmi	TT	81	876	95	854	0.2500	0.84	0.63	1.13	0.0810	A	0.17	T	0.83
  hCV1682755	rs9424977	NEGR1	rmi	CT+CC	73	941	112	893	0.0021	0.63	0.47	0.85	0.0780	C	0.48	T	0.52
  hCV1682755	rs9424977	NEGR1	rmi	TT	38	347	36	331	0.9200	1.02	0.65	1.62	0.0780	C	0.48	T	0.52
  hCV27480853	rs3766430	SSBP3	rmi	TC+TT	81	1029	124	992	0.0022	0.65	0.49	0.85	0.0820	C	0.44	T	0.56
  hCV27480853	rs3766430	SSBP3	rmi	CC	30	262	24	233	0.7200	1.10	0.64	1.88	0.0820	C	0.44	T	0.56
  hCV2948766	rs4684343	CNTN4	rmi	GA+GG	85	1042	129	1010	0.0022	0.65	0.50	0.86	0.0660	A	0.43	G	0.57
  hCV2948766	rs4684343	CNTN4	rmi	AA	25	244	18	213	0.5200	1.22	0.67	2.24	0.0660	A	0.43	G	0.57
  hCV30534667	rs4996259	MAGI2	rmi	AG+AA	47	667	79	595	0.0012	0.55	0.38	0.79	0.0330	A	0.30	G	0.70
  hCV30534667	rs4996259	MAGI2	rmi	GG	64	624	69	630	0.7300	0.94	0.67	1.32	0.0330	A	0.30	G	0.70
  hCV30764105	rs12521915	ITGA2	rmi	GC+GG	57	800	94	727	0.0008	0.57	0.41	0.79	0.0240	C	0.63	G	0.37
  hCV30764105	rs12521915	ITGA2	rmi	CC	54	491	54	498	0.9700	1.01	0.69	1.47	0.0240	C	0.63	G	0.37
  hCV11231076	rs4857855		rmi	CT+TT	46	405	42	414	0.6200	1.11	0.73	1.69	0.0130	C	0.82	T	0.18
  hCV11231076	rs4857855		rmi	CC	65	885	106	809	0.0005	0.58	0.42	0.79	0.0130	C	0.82	T	0.18
  hCV11466079	rs157580	TOMM40	rmi	GA+AA	98	1081	119	1029	0.1000	0.80	0.61	1.04	0.0830	A	0.61	G	0.39
  hCV11466079	rs157580	TOMM40	rmi	GG	13	207	29	195	0.0120	0.43	0.23	0.83	0.0830	A	0.61	G	0.39
  hCV11592758	rs6265	BDNF	rmi	CT+TT	48	434	44	407	0.9000	1.03	0.68	1.54	0.0360	C	0.82	T	0.18
  hCV11592758	rs6265	BDNF	rmi	CC	61	880	101	830	0.0010	0.59	0.43	0.81	0.0360	C	0.82	T	0.18
  hCV11703905	rs1169301	TCF1	rmi	CT+TT	67	661	72	632	0.5000	0.89	0.64	1.25	0.0730	C	0.69	T	0.31
  hCV11703905	rs1169301	TCF1	rmi	CC	44	627	76	593	0.0026	0.57	0.39	0.82	0.0730	C	0.69	T	0.31
  hCV2195496	rs4982795		rmi	CT+TT	92	1020	112	989	0.1300	0.81	0.61	1.06	0.0950	C	0.44	T	0.56
  hCV2195496	rs4982795		rmi	CC	18	266	35	234	0.0099	0.47	0.27	0.84	0.0950	C	0.44	T	0.56
  hCV28960526	rs6853079	TSPAN5	rmi	AT+TT	51	495	49	494	0.8400	1.04	0.70	1.54	0.0220	A	0.77	T	0.23
  hCV28960526	rs6853079	TSPAN5	rmi	AA	60	796	99	732	0.0007	0.57	0.42	0.79	0.0220	A	0.77	T	0.23
  hCV29480044	rs10516433	TSPAN5	rmi	CT+TT	51	491	49	494	0.8100	1.05	0.71	1.55	0.0210	C	0.78	T	0.22
  hCV29480044	rs10516433	TSPAN5	rmi	CC	60	795	99	733	0.0008	0.58	0.42	0.79	0.0210	C	0.78	T	0.22
  hCV30136303	rs6914527		rmi	GC+CC	77	797	85	813	0.6000	0.92	0.68	1.25	0.0130	C	0.40	G	0.60
  hCV30136303	rs6914527		rmi	GG	34	493	63	412	0.0005	0.48	0.31	0.72	0.0130	C	0.40	G	0.60
  hCV30454150	rs10516434	TSPAN5	rmi	CT+TT	51	489	49	491	0.8200	1.05	0.71	1.55	0.0200	C	0.78	T	0.22
  hCV30454150	rs10516434	TSPAN5	rmi	CC	60	799	99	734	0.0007	0.57	0.42	0.79	0.0200	C	0.78	T	0.22
  hCV487868	rs6439132		rmi	TC+CC	60	573	63	563	0.7200	0.94	0.66	1.34	0.0490	C	0.26	T	0.74
  hCV487868	rs6439132		rmi	TT	51	718	85	662	0.0015	0.57	0.40	0.81	0.0490	C	0.26	T	0.74
  hCV904974	rs439401		rmi	TC+CC	101	1090	122	1025	0.0790	0.79	0.61	1.03	0.0980	C	0.61	T	0.39
  hCV904974	rs439401		rmi	TT	10	194	26	199	0.0160	0.41	0.20	0.85	0.0980	C	0.61	T	0.39
  hCV15954645	rs2954029		rmi	AA	36	376	31	344	0.8600	1.04	0.65	1.69	0.0421	A	0.53	T	0.47
  hCV15954645	rs2954029		rmi	AT	46	613	89	601	0.0004	0.53	0.37	0.75	0.0421	A	0.53	T	0.47
  hCV15954645	rs2954029		rmi	TT	28	296	28	278	0.8200	0.94	0.56	1.59	0.0421	A	0.53	T	0.47
  hCV29684678	rs10486788		rmi	CC	9	89	6	105	0.3000	1.72	0.61	4.83	0.0984	C	0.28	G	0.72
  hCV29684678	rs10486788		rmi	CG	40	526	67	481	0.0045	0.57	0.38	0.84	0.0984	C	0.28	G	0.72
  hCV29684678	rs10486788		rmi	GG	62	672	74	637	0.2000	0.80	0.57	1.12	0.0984	C	0.28	G	0.72
  hCV621313	rs471364	C9orf52	rmi	CC	2	16	1	24	0.4300	2.64	0.24	29.12	0.0972	C	0.13	T	0.87
  hCV621313	rs471364	C9orf52	rmi	CT	20	288	41	263	0.0048	0.46	0.27	0.79	0.0972	C	0.13	T	0.87
  hCV621313	rs471364	C9orf52	rmi	TT	89	984	106	936	0.1500	0.81	0.61	1.08	0.0972	C	0.13	T	0.87
  hDV70938014	rs17321515		rmi	AA	34	363	31	328	0.9200	0.98	0.60	1.59	0.0770	A	0.52	G	0.48
  hDV70938014	rs17321515		rmi	AG	47	620	88	612	0.0009	0.55	0.38	0.78	0.0770	A	0.52	G	0.48
  hDV70938014	rs17321515		rmi	GG	30	309	29	287	0.8800	0.96	0.58	1.60	0.0770	A	0.52	G	0.48
  hCV11446935	rs2409722	XKR6	rmi	GG	39	325	39	337	0.8400	0.67	0.67	1.63	0.0560	G	0.51	T	0.49
  hCV11446935	rs2409722	XKR6	rmi	GT+TT	72	960	109	888	0.0019	0.46	0.46	0.84	0.0560	G	0.51	T	0.49
  hCV10048483	rs2145270		rmi	CC	22	187	16	166	0.5000	0.66	0.66	2.38	0.0730	C	0.38	T	0.62
  hCV10048483	rs2145270		rmi	CT+TT	89	1103	132	1059	0.0023	0.50	0.50	0.86	0.0730	C	0.38	T	0.62

• TABLE 22
  SNPs Associated with Risk of CHD in Placebo Arm of CARE

  						TOTAL
  				Allele 2	EVENTS	PATIENTS
  		gene		(reference	(placebo	(placebo	Allele 1
  hCV	rs	symbol	Allele1	allele)	arm)	arm)	Freq.
  hCV11513719	rs2967605	ELAVL1	T	C	166	1367	0.18
  hCV1323634	rs287475		T	C	167	1372	0.57
  hCV1323669	rs287354		G	A	166	1373	0.56
  hCV1729928	rs10509384	KCNMA1	A	G	167	1368	0.66
  hCV2221541	rs739161		T	C	167	1373	0.71
  hCV260164	rs6754295		T	G	167	1373	0.76
  hCV29011391	rs7557067		A	G	167	1373	0.76
  hCV29135108	rs6743779	KLF7	C	A	167	1372	0.32
  hCV3242952	rs2000571		A	G	167	1372	0.22
  hCV7537517	rs1501908		C	G	166	1372	0.64
  hCV7910239	rs1541296	FVT1	A	G	166	1370	0.66
  hCV11466848	rs1805419	BAX	A	G	167	1373	0.28
  hCV2554721	rs7315519	RPH3A	A	G	167	1372	0.46
  hCV2762168	rs3939286		T	C	167	1371	0.26
  hCV31237961	rs11950562	SLC22A4	A	C	167	1371	0.54
  hCV3168675	rs469930		G	A	167	1371	0.36
  hCV3170445	rs272893	SLC22A4	T	C	167	1373	0.39
  hCV610861	rs636887		T	C	167	1373	0.57
  hCV8785824	rs1412426		A	C	167	1369	0.33
  hCV8785827	rs992969	IL33	A	G	167	1371	0.26
  hDV70797856	rs17006217		C	T	167	1373	0.11
  hCV1026586	rs673548	APOB	G	A	167	1372	0.77
  hCV11568668	rs1317538	KCNQ5	A	G	166	1374	0.48
  hCV1489995	rs4013819	LOC392281	G	C	167	1372	0.37
  hCV1948599	rs504527	CSMD2	C	A	167	1370	0.51
  hCV601962	rs544543	ZNF568	G	A	167	1371	0.38
  hCV601961	rs568654	ZNF568	A	G	167	1373	0.38
  hCV8369472	rs1447351	MTNR1B	G	A	167	1373	0.53
  hCV461035	rs7746448		T	C	167	1373	0.60
  hCV30606396	rs10438978		T	C	167	1372	0.17
  hCV22303	rs4552916		G	A	167	1373	0.22
  hCV11856381	rs2197089		A	G	148	1371	0.55
  hCV15954645	rs2954029		A	T	148	1371	0.53
  hCV28960526	rs6853079	TSPAN5	A	T	148	1374	0.78
  hCV29480044	rs10516433	TSPAN5	C	T	148	1375	0.78
  hCV29684678	rs10486788		C	G	147	1370	0.28
  hCV30454150	rs10516434	TSPAN5	C	T	148	1373	0.78
  hCV30136303	rs6914527		G	C	148	1373	0.60
  hCV2195496	rs4982795		c	T	147	1370	0.44
  hCV2948766	rs4684343	CNTN4	G	A	147	1370	0.58
  hCV1253630	rs2071307	ELN	A	G	162	1371	0.41
  hCV15746640	rs41271951	CTSS	G	A	165	1379	0.08
  hCV16044337	rs2569491	KLK14	A	G	164	1373	0.31
  hCV16179493	rs2108622	CYP4F2	T	C	165	1379	0.31
  hCV1647371	rs3025000	VEGFA	T	C	161	1354	0.33
  hCV1843175	rs3745535	KLK10	A	C	165	1378	0.36
  hCV2230606	rs13268	FBLN1	G	A	164	1380	0.02
  hCV2276802	rs381418	GBA	C	A	164	1380	0.37
  hCV2536595	rs704	VTN	A	G	165	1383	0.47
  hCV25472673	rs1805081	NPC1	C	T	164	1380	0.39
  hCV25596880	rs4647297	CASP2	C	G	165	1380	0.06
  hCV25603879	rs11542844	SCNN1A	T	C	165	1376	0.03
  hCV25610819	rs8176740		T	A	165	1374	0.23
  hCV25614016	rs7607759	CAPN10	G	A	165	1379	0.16
  hCV25617571	rs2232580	LBP	T	C	165	1382	0.08
  hCV25629396	rs3729823	MYH7	C	G	164	1378	0.01
  hCV25631989	rs1135983	ATF6	T	C	158	1346	0.08
  hCV25644901		ITGA9	G	A	165	1379	0.05
  hCV25926178	rs12882130	MARK3	G	C	161	1352	0.38
  hCV25926771	rs4906321	MARK3	C	T	161	1350	0.31
  hCV25927605		HLA-DPA1	T	C	165	1375	0.03
  hCV25941408	rs28497577	MYLK	T	G	163	1381	0.10
  hCV2633049	rs2302006	CCL24	G	T	164	1378	0.20
  hCV2658421	rs3176975	APOH	A	C	164	1376	0.23
  hCV2741051	rs2230806	ABCA1	T	C	165	1382	0.28
  hCV2741083	rs4149313	ABCA1	C	T	165	1381	0.13
  hCV2983035	rs9527026	KL	A	G	163	1377	0.15
  hCV2983036	rs9527025	KL	C	G	165	1376	0.15
  hCV3026189	rs11739136	KCNIP1	T	C	165	1383	0.10
  hCV435368	rs2812	PECAM1	T	C	164	1380	0.47
  hCV529706	rs428785	ADAMTS1	C	G	164	1375	0.24
  hCV529710	rs402007	ADAMTS1	C	G	165	1382	0.24
  hCV5478	rs1800574	TCF1	T	C	165	1382	0.03
  hCV7499212	rs1800127	LRP1	T	C	165	1379	0.02
  hCV7514870	rs1041981	LTA	A	C	165	1381	0.33
  hCV7577801	rs11876	SLC9A3R2	T	C	165	1374	0.22
  hCV783184	rs510335		T	G	164	1379	0.12
  hCV7900503	rs3732379	CX3CR1	T	C	165	1381	0.28
  hCV8718197	rs1050998	CXCL16	G	A	165	1383	0.44
  hCV8784787	rs688976		A	C	165	1381	0.23
  hCV8901525	rs861539	KLC1	A	G	161	1352	0.37
  hCV8921288	rs1060621	GAPDH	C	A	158	1347	0.20
  hCV9077561	rs1801274	FCGR2A	G	A	165	1381	0.50
  hCV2741051	rs2230806	ABCA1	T	C	165	1382	0.28
  hCV435368	rs2812	PECAM1	T	C	164	1380	0.47
  hCV8921288	rs1060621	GAPDH	C	A	158	1347	0.20
  hCV11689916	rs4531	DBH	A	T	158	1314	0.48
  hCV12020339			T	G	165	1374	0.08
  hCV1243283	rs1716	ITGAE	A	G	165	1379	0.33
  hCV1552894	rs434473	ALOX12	G	A	165	1377	0.42
  hCV1552900	rs1126667	ALOX12	A	G	165	1379	0.42
  hCV15851335	rs17610395	CPT1A	T	C	164	1379	0.07
  hCV15954277	rs2236379	PRKCQ	A	G	165	1383	0.26
  hCV16173091	rs2241883	FABP1	C	T	165	1381	0.32
  hCV1741111	rs1764391	C1orf212	T	C	165	1380	0.30
  hCV2143205	rs9666607	CD44	A	G	165	1383	0.32
  hCV22274761	rs11575194	IGFBP5	A	G	165	1378	0.04
  hCV2503034	rs1132356	BAIAP3	A	C	164	1372	0.11
  hCV2531086	rs10406069	CD22	A	G	165	1379	0.21
  hCV25473098	rs2241883	FABP1	G	A	163	1371	0.31
  hCV25610774	rs8176748		T	C	165	1382	0.23
  hCV25637309	rs3204849	CCRL2	A	T	165	1378	0.39
  hCV25651174	rs9277356	HLA-DPB1	G	A	165	1375	0.30
  hCV2769554	rs1805010	IL4R	G	A	165	1378	0.46
  hCV370782	rs9841174	SERPINI2	C	T	165	1376	0.38
  hCV549926	rs1057141	Tap1or	C	T	165	1376	0.16
  hCV7490135	rs1805082	NPC1	C	T	165	1376	0.47
  hCV8804621	rs1390938	SLC18A1	A	G	164	1376	0.25
  hCV8851065	rs9277343	HLA-DPA1	G	C	165	1383	0.28
  hCV9604851	rs1805002	CCKBR	A	G	165	1380	0.05
  hCV997884	rs512770		A	G	164	1370	0.20
  hCV3135085	rs10795446	CUBN	G	T	164	1370	0.33
  hCV3215409	rs267561	ITGA9	G	A	165	1381	0.42
  hCV7494810	rs1058587	GDF15	G	C	165	1379	0.25
  hCV783138	rs6046	F10	A	G	163	1377	0.11
  hCV795442	rs375947	IL12RB1	G	A	164	1381	0.32
  hCV818008	rs5918	ITGB3	C	T	165	1381	0.15
  	Allele 2
  hCV	Freq.	HR	HR95L	HR95U	P value	Model	Endpoint
  hCV11513719	0.82	1.49	1.09	2.03	0.012	dom	endpt1
  hCV1323634	0.43	1.90	1.17	3.10	0.01	dom	endpt1
  hCV1323669	0.44	1.62	1.04	2.54	0.034	dom	endpt1
  hCV1729928	0.34	1.59	0.92	2.75	0.096	dom	endpt1
  hCV2221541	0.29	0.65	0.39	1.07	0.087	dom	endpt1
  hCV260164	0.24	2.37	0.88	6.39	0.088	dom	endpt1
  hCV29011391	0.24	2.34	0.87	6.30	0.094	dom	endpt1
  hCV29135108	0.68	1.42	1.04	1.94	0.027	dom	endpt1
  hCV3242952	0.78	1.31	0.96	1.78	0.084	dom	endpt1
  hCV7537517	0.36	2.37	1.25	4.48	0.0083	dom	endpt1
  hCV7910239	0.34	1.64	0.95	2.83	0.077	dom	endpt1
  hCV11466848	0.72	1.37	1.01	1.87	0.041	dom	endpt1
  hCV2554721	0.54	1.45	1.01	2.09	0.046	dom	endpt1
  hCV2762168	0.74	1.47	1.09	2.00	0.013	dom	endpt1
  hCV31237961	0.46	1.62	1.05	2.49	0.03	dom	endpt1
  hCV3168675	0.64	1.31	0.95	1.80	0.097	dom	endpt1
  hCV3170445	0.61	1.62	1.15	2.27	0.0056	dom	endpt1
  hCV610861	0.43	1.61	1.02	2.54	0.041	dom	endpt1
  hCV8785824	0.67	1.45	1.06	1.98	0.021	dom	endpt1
  hCV8785827	0.74	1.49	1.10	2.02	0.01	dom	endpt1
  hDV70797856	0.89	1.42	1.01	2.00	0.044	dom	endpt1
  hCV1026586	0.23	1.47	1.06	2.04	0.02	rec	endpt1
  hCV11568668	0.52	1.34	0.96	1.87	0.084	rec	endpt1
  hCV1489995	0.63	1.51	1.04	2.20	0.032	rec	endpt1
  hCV1948599	0.49	1.44	1.04	1.99	0.03	rec	endpt1
  hCV601962	0.62	1.44	0.98	2.11	0.066	rec	endpt1
  hCV601961	0.62	1.46	0.99	2.14	0.055	rec	endpt1
  hCV8369472	0.47	1.44	1.05	1.98	0.023	rec	endpt1
  hCV461035	0.40	1.30	0.96	1.77	0.094	rec	endpt1
  hCV30606396	0.83	1.35	0.98	1.87	0.064	het	endpt1
  hCV22303	0.78	1.32	0.96	1.81	0.087	het	endpt1
  hCV11856381	0.45	1.70	1.05	2.75	0.031	dom	rmi
  hCV15954645	0.47	0.70	0.47	1.03	0.072	rec	rmi
  hCV28960526	0.22	1.36	0.96	1.91	0.082	rec	rmi
  hCV29480044	0.22	1.35	0.96	1.91	0.083	rec	rmi
  hCV29684678	0.72	0.46	0.20	1.04	0.063	rec	rmi
  hCV30454150	0.22	1.34	0.95	1.89	0.09	rec	rmi
  hCV30136303	0.40	1.42	1.02	1.96	0.036	rec	rmi
  hCV2195496	0.56	0.69	0.48	1.00	0.05	het	rmi
  hCV2948766	0.42	1.62	0.97	2.69	0.064	het	rmi
  hCV1253630	0.59	0.71	0.522	0.977	0.0354	dom	endpt1
  hCV15746640	0.92	0.55	0.322	0.932	0.0263	dom	endpt1
  hCV16044337	0.69	1.35	0.989	1.846	0.0587	dom	endpt1
  hCV16179493	0.69	0.76	0.559	1.032	0.0788	dom	endpt1
  hCV1647371	0.67	0.7	0.51	0.949	0.0218	dom	endpt1
  hCV1843175	0.64	1.4	1.016	1.921	0.0394	dom	endpt1
  hCV2230606	0.98	0.35	0.112	1.097	0.0717	dom	endpt1
  hCV2276802	0.63	0.72	0.518	0.994	0.0459	dom	endpt1
  hCV2536595	0.53	1.71	1.174	2.497	0.0052	dom	endpt1
  hCV25472673	0.61	1.47	1.048	2.062	0.0257	dom	endpt1
  hCV25596880	0.94	0.6	0.335	1.085	0.0914	dom	endpt1
  hCV25603879	0.97	0.43	0.176	1.046	0.0628	dom	endpt1
  hCV25610819	0.77	0.76	0.556	1.051	0.0988	dom	endpt1
  hCV25614016	0.84	0.63	0.436	0.92	0.0164	dom	endpt1
  hCV25617571	0.92	1.58	1.077	2.311	0.0191	dom	endpt1
  hCV25629396	0.99	0.16	0.023	1.163	0.0705	dom	endpt1
  hCV25631989	0.92	0.5	0.286	0.89	0.0182	dom	endpt1
  hCV25644901	0.95	1.93	1.272	2.939	0.002	dom	endpt1
  hCV25926178	0.62	1.45	1.041	2.029	0.0281	dom	endpt1
  hCV25926771	0.69	1.57	1.116	2.203	0.0094	dom	endpt1
  hCV25927605	0.97	0.3	0.094	0.927	0.0366	dom	endpt1
  hCV25941408	0.90	1.44	1.003	2.074	0.048	dom	endpt1
  hCV2633049	0.81	0.7	0.498	0.98	0.038	dom	endpt1
  hCV2658421	0.77	1.35	0.995	1.836	0.0539	dom	endpt1
  hCV2741051	0.72	0.65	0.471	0.884	0.0064	dom	endpt1
  hCV2741083	0.87	0.54	0.349	0.842	0.0064	dom	endpt1
  hCV2983035	0.85	1.34	0.968	1.865	0.0771	dom	endpt1
  hCV2983036	0.85	1.32	0.952	1.83	0.096	dom	endpt1
  hCV3026189	0.90	0.69	0.442	1.067	0.095	dom	endpt1
  hCV435368	0.53	1.61	1.106	2.353	0.013	dom	endpt1
  hCV529706	0.76	1.42	1.043	1.923	0.026	dom	endpt1
  hCV529710	0.76	1.42	1.05	1.933	0.023	dom	endpt1
  hCV5478	0.97	0.38	0.142	1.032	0.0578	dom	endpt1
  hCV7499212	0.98	1.87	1.081	3.232	0.0252	dom	endpt1
  hCV7514870	0.67	1.32	0.968	1.808	0.0791	dom	endpt1
  hCV7577801	0.78	0.66	0.475	0.93	0.017	dom	endpt1
  hCV783184	0.88	0.69	0.459	1.048	0.0821	dom	endpt1
  hCV7900503	0.72	0.72	0.524	0.975	0.034	dom	endpt1
  hCV8718197	0.56	0.71	0.519	0.969	0.0311	dom	endpt1
  hCV8784787	0.77	0.76	0.552	1.044	0.0897	dom	endpt1
  hCV8901525	0.63	0.73	0.534	0.991	0.0439	dom	endpt1
  hCV8921288	0.80	1.6	1.169	2.186	0.0033	dom	endpt1
  hCV9077561	0.50	1.47	1	2.164	0.0499	dom	endpt1
  hCV2741051	0.72	0.65	0.471	0.884	0.0064	dom	endpt1
  hCV435368	0.53	1.61	1.106	2.353	0.013	dom	endpt1
  hCV8921288	0.80	1.6	1.169	2.186	0.0033	dom	endpt1
  hCV11689916	0.52	1.33	0.963	1.849	0.0827	rec	endpt1
  hCV12020339	0.92	2.92	0.93	9.135	0.0663	rec	endpt1
  hCV1243283	0.67	1.57	1.012	2.444	0.0442	rec	endpt1
  hCV1552894	0.58	1.49	1.05	2.104	0.0254	rec	endpt1
  hCV1552900	0.58	1.48	1.047	2.098	0.0265	rec	endpt1
  hCV15851335	0.93	4.44	1.101	17.895	0.0362	rec	endpt1
  hCV15954277	0.74	0.24	0.076	0.75	0.0141	rec	endpt1
  hCV16173091	0.68	0.53	0.282	1.013	0.0546	rec	endpt1
  hCV1741111	0.70	0.46	0.203	1.034	0.0602	rec	endpt1
  hCV2143205	0.68	0.55	0.282	1.08	0.0828	rec	endpt1
  hCV22274761	0.96	16.7	2.327	119.75	0.0051	rec	endpt1
  hCV2503034	0.89	3.54	1.13	11.098	0.03	rec	endpt1
  hCV2531086	0.79	0.31	0.076	1.232	0.0955	rec	endpt1
  hCV25473098	0.69	0.59	0.319	1.084	0.0889	rec	endpt1
  hCV25610774	0.77	0.23	0.056	0.918	0.0375	rec	endpt1
  hCV25637309	0.61	0.47	0.278	0.805	0.0057	rec	endpt1
  hCV25651174	0.70	0.46	0.216	0.979	0.044	rec	endpt1
  hCV2769554	0.54	0.51	0.324	0.81	0.0042	rec	endpt1
  hCV370782	0.62	0.54	0.319	0.924	0.0243	rec	endpt1
  hCV549926	0.84	2.05	1.006	4.164	0.0481	rec	endpt1
  hCV7490135	0.53	1.38	0.981	1.929	0.0645	rec	endpt1
  hCV8804621	0.75	0.38	0.141	1.021	0.0551	rec	endpt1
  hCV8851065	0.72	0.51	0.24	1.093	0.0836	rec	endpt1
  hCV9604851	0.95	5.46	1.742	17.11	0.0036	rec	endpt1
  hCV997884	0.80	0.24	0.059	0.957	0.0432	rec	endpt1
  hCV3135085	0.67	0.74	0.533	1.034	0.0781	het	endpt1
  hCV3215409	0.58	1.48	0.955	2.28	0.0797	hom	endpt1
  hCV7494810	0.75	1.35	0.987	1.844	0.0608	het	endpt1
  hCV783138	0.89	0.66	0.417	1.045	0.0762	het	endpt1
  hCV795442	0.68	0.74	0.535	1.032	0.0765	het	endpt1
  hCV818008	0.85	1.33	0.956	1.839	0.0914	het	endpt1

Claims (26)

1. A method of determining whether a human has an altered risk for cardiovascular disease (CVD), comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement, wherein said polymorphism indicates said human has an altered risk for CVD.

2. The method of claim 1, wherein said CVD is coronary heart disease (CHD).

3. The method of claim 2, wherein said CHD is myocardial infarction.

4. The method of claim 1, wherein said polymorphism is in the GOSR2 gene and wherein said CVD is hypertension.

5-10. (canceled)

11. The method of claim 1, wherein said testing step comprises nucleic acid amplification.

12. The method of claim 11, wherein said nucleic acid amplification is carried out by polymerase chain reaction.

13-14. (canceled)

15. The method of claim 1, wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE).

16. The method of claim 1, wherein said testing is performed using an allele-specific method.

17. The method of claim 16, wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification.

18. The method of claim 17, wherein said method is performed using an allele-specific primer provided in Table 5.

19. (canceled)

20. The method of claim 1, further comprising correlating the presence of said polymorphism with said human's responsiveness to a therapeutic agent.

21. The method of claim 20, wherein said therapeutic agent comprises an HMG-CoA reductase inhibitor.

22. The method of claim 21, wherein said polymorphism is selected from the group consisting of the polymorphisms provided in Table 22.

23-25. (canceled)

26. A method of determining whether a human will respond to an HMG-CoA reductase inhibitor for reducing risk for cardiovascular disease (CVD), comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms provided in Table 21.

27. The method of claim 26, further comprising administering said HMG-CoA reductase inhibitor to said human.

28. (canceled)

29. A method for reducing risk of cardiovascular disease (CVD) in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for CVD due to the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement.

30. The method of claim 29, wherein said method comprises testing nucleic acid from said human for the presence or absence of said polymorphism.

31. The method of claim 29, wherein said CVD is coronary heart disease (CHD).

32. The method of claim 31, wherein said CHD is myocardial infarction.

33. The method of claim 29, wherein said therapeutic agent comprises an HMG-CoA reductase inhibitor.

34-45. (canceled)