Background Exposure to road traffic noise has been linked to cardiometabolic complications, such as elevated blood pressure and glucose dysregulation. However, epidemiologic evidence linking road traffic noise to diabetes mellitus and hypertension remains scarce. We examined associations between road traffic noise and the incidence of diabetes mellitus and hypertension in Toronto, Canada. Methods and Results Using the Ontario Population Health and Environment Cohort, we conducted a retrospective, population-based cohort study of long-term residents of Toronto, aged 35 to 100 years, who were registered for provincial publicly funded health insurance, and were without a history of hypertension (n=701 174) or diabetes mellitus (n=914 607). Road traffic noise exposure levels were assessed by the equivalent continuous A-weighted sound pressure level (dBA) for the 24-hour day and the equivalent continuous A-weighted sound pressure level for the night (11 pm-7am). Noise exposures were assigned to subjects according to their annual residential postal codes during the 15-year follow-up. We used random-effect Cox proportional hazards models adjusting for personal and area-level characteristics. From 2001 to 2015, each interquartile range increase in the equivalent continuous A-weighted sound pressure level (dBA) for the 24-hour day (10.0 dBA) was associated with an 8% increase in incident diabetes mellitus (95% CI, 1.07-1.09) and a 2% increase in hypertension (95% CI, 1.01-1.03). We obtained similar estimates with the equivalent continuous A-weighted sound pressure level for the night (11 pm-7am). These results were robust to all sensitivity analyses conducted, including further adjusting for traffic-related air pollutants (ultrafine particles and nitrogen dioxide). For both hypertension and diabetes mellitus, we observed stronger associations with the equivalent continuous A-weighted sound pressure level (dBA) for the 24-hour day among women and younger adults (aged <60 years). Conclusions Long-term exposure to road traffic noise was associated with an increased incidence of diabetes mellitus and hypertension in Toronto.

The independent and joint effects of within- and between-city contrasts in air pollution on mortality have been investigated rarely. To examine the differential effects of between- versus within-city contrasts in pollution exposure, we used both ambient measurements and land use regression models to assess associations with mortality and exposure to nitrogen dioxide (NO2) among ~735,600 adults in 10 of the largest Canadian cities. We estimated exposure contrasts partitioned into within- and between-city contrasts, and the sum of these as overall exposures, for every year from 1984 to 2006. Residential histories allowed us to follow subjects annually during the study period. We calculated hazard ratios (HRs) adjusted for many personal and contextual variables. In fully-adjusted, random-effects models, we found positive associations between overall NO2 exposures and mortality from non-accidental causes (HR per 5 p.p.b.: 1.05; 95% confidence interval (CI): 1.03-1.07), cardiovascular disease (HR per 5 p.p.b.: 1.04; 95% CI: 1.01-1.06), ischaemic heart disease (HR per 5 p.p.b.: 1.05; 95% CI: 1.02-1.08) and respiratory disease (HR per 5 p.p.b.: 1.04; 95% CI: 0.99-1.08), but not from cerebrovascular disease (HR per 5 p.p.b.: 1.01; 95% CI: 0.96-1.06). We found that most of these associations were determined by within-city contrasts, as opposed to by between-city contrasts in NO2. Our results suggest that variation in NO2 concentrations within a city may represent a more toxic mixture of pollution than variation between cities.

Background

Survivors of acute myocardial infarction (AMI) are at increased risk of dying within several hours to days following exposure to elevated levels of ambient air pollution. Little is known, however, about the influence of long-term (months to years) air pollution exposure on survival after AMI.

Objective

We conducted a population-based cohort study to determine the impact of long-term exposure to fine particulate matter ≤ 2.5 μm in diameter (PM2.5) on post-AMI survival.

Methods

We assembled a cohort of 8,873 AMI patients who were admitted to 1 of 86 hospital corporations across Ontario, Canada in 1999-2001. Mortality follow-up for this cohort extended through 2011. Cumulative time-weighted exposures to PM2.5 were derived from satellite observations based on participants' annual residences during follow-up. We used standard and multilevel spatial random-effects Cox proportional hazards models and adjusted for potential confounders.

Results

Between 1999 and 2011, we identified 4,016 nonaccidental deaths, of which 2,147 were from any cardiovascular disease, 1,650 from ischemic heart disease, and 675 from AMI. For each 10-μg/m3 increase in PM2.5, the adjusted hazard ratio (HR10) of nonaccidental mortality was 1.22 [95% confidence interval (CI): 1.03, 1.45]. The association with PM2.5 was robust to sensitivity analyses and appeared stronger for cardiovascular-related mortality: ischemic heart (HR10 = 1.43; 95% CI: 1.12, 1.83) and AMI (HR10 = 1.64; 95% CI: 1.13, 2.40). We estimated that 12.4% of nonaccidental deaths (or 497 deaths) could have been averted if the lowest measured concentration in an urban area (4 μg/m3) had been achieved at all locations over the course of the study.

Conclusions

Long-term air pollution exposure adversely affects the survival of AMI patients.

Citation

Chen H, Burnett RT, Copes R, Kwong JC, Villeneuve PJ, Goldberg MS, Brook RD, van Donkelaar A, Jerrett M, Martin RV, Brook JR, Kopp A, Tu JV. 2016. Ambient fine particulate matter and mortality among survivors of myocardial infarction: population-based cohort study. Environ Health Perspect 124:1421-1428; https://dx.doi.org/10.1289/EHP185.

Background

Few studies examining the associations between long-term exposure to ambient air pollution and mortality have considered multiple pollutants when assessing changes in exposure due to residential mobility during follow-up.

Objective

We investigated associations between cause-specific mortality and ambient concentrations of fine particulate matter (≤ 2.5 μm; PM2.5), ozone (O3), and nitrogen dioxide (NO2) in a national cohort of about 2.5 million Canadians.

Methods

We assigned estimates of annual concentrations of these pollutants to the residential postal codes of subjects for each year during 16 years of follow-up. Historical tax data allowed us to track subjects' residential postal code annually. We estimated hazard ratios (HRs) for each pollutant separately and adjusted for the other pollutants. We also estimated the product of the three HRs as a measure of the cumulative association with mortality for several causes of death for an increment of the mean minus the 5th percentile of each pollutant: 5.0 μg/m3 for PM2.5, 9.5 ppb for O3, and 8.1 ppb for NO2.

Results

PM2.5, O3, and NO2 were associated with nonaccidental and cause-specific mortality in single-pollutant models. Exposure to PM2.5 alone was not sufficient to fully characterize the toxicity of the atmospheric mix or to fully explain the risk of mortality associated with exposure to ambient pollution. Assuming additive associations, the estimated HR for nonaccidental mortality corresponding to a change in exposure from the mean to the 5th percentile for all three pollutants together was 1.075 (95% CI: 1.067, 1.084). Accounting for residential mobility had only a limited impact on the association between mortality and PM2.5 and O3, but increased associations with NO2.

Conclusions

In this large, national-level cohort, we found positive associations between several common causes of death and exposure to PM2.5, O3, and NO2.

Citation

Crouse DL, Peters PA, Hystad P, Brook JR, van Donkelaar A, Martin RV, Villeneuve PJ, Jerrett M, Goldberg MS, Pope CA III, Brauer M, Brook RD, Robichaud A, Menard R, Burnett RT. 2015. Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian Census Health and Environment Cohort (CanCHEC). Environ Health Perspect 123:1180-1186; https://dx.doi.org/10.1289/ehp.1409276.

Background

Living in greener areas of cities was linked to increased physical activity levels, improved mental well-being, and lowered harmful environmental exposures, all of which may affect human health. However, whether living in greener areas may be associated with lower risk of cardiovascular disease incidence, progression, and premature mortality is unclear.

Objectives

We conducted a cohort study to examine the associations between residential green spaces and the incidence of acute myocardial infarction (AMI) and heart failure (HF), post-AMI and HF hospital readmissions, and mortality.

Methods

We simultaneously followed four large population-based cohorts in Ontario, Canada, including the entire adult population, adults free of AMI and HF, and survivors of AMI or HF from 2000 to 2014. We estimated residential exposure to green spaces using satellite-derived observations and ascertained health outcomes using validated disease registries. We estimated the associations using spatial random-effects Cox proportional hazards models. We conducted various sensitivity analyses, including further adjusting for property values and performing exploratory mediation analysis.

Results

Each interquartile range increase in residential greenness was associated with a 7% [95% confidence interval (CI): 4%, 9%] decrease in incident AMI and a 6% (95% CI: 4%, 7%) decrease in incident HF. Residential greenness was linked to a ∼10% decrease in cardiovascular mortality in both adults free of AMI and HF and the entire adult population. These associations remained consistent in sensitivity analyses and were accentuated among younger adults. Additionally, we estimated that the decreases in AMI and HF incidence associated with residential greenness explained ∼53% of the protective association between residential greenness and cardiovascular mortality. Conversely, residential greenness was not associated with any delay in readmission or mortality among AMI and HF patients.

Conclusions

Living in urban areas with more green spaces was associated with improved cardiovascular health in people free of AMI and HF but not among individuals who have already developed these conditions. https://doi.org/10.1289/EHP6161.

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER⁺) breast cancer (per-g allele OR ER⁺ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10^-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER^-) breast cancer (lead SNP rs6864776: per-a allele OR ER^- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10^-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER⁺ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10^-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.