Common genetic variation, residential proximity to traffic exposure, and left ventricular mass: the multi-ethnic study of atherosclerosis

Abstract

Background: Elevated left ventricular mass (LVM) is a strong predictor of negative cardiovascular outcomes, including heart failure, stroke, and sudden cardiac death. A relationship between close (< 50 m compared with > 150 m) residential proximity to major roadways and higher LVM has previously been described, but the mechanistic pathways that are involved in this relationship are not known. Understanding genetic factors that influence susceptibility to these effects may provide insight into relevant mechanistic pathways.

Objective: We set out to determine whether genetic polymorphisms in genes affecting vascular and autonomic function, blood pressure, or inflammation influence the relationship between traffic proximity and LVM.

Methods: This was a cross-sectional study of 1,376 genotyped participants in the Multi-Ethnic Study of Atherosclerosis, with cardiac magnetic resonance imaging performed between 2000 and 2002. The impact of tagged single-nucleotide polymorphisms (tagSNPs) and inferred haplotypes in 12 candidate genes (ACE, ADRB2, AGT, AGTR1, ALOX15, EDN1, GRK4, PTGS1, PTGS2, TLR4, VEGFA, and VEGFB) on the relationship between residential proximity to major roadways and LVM was analyzed using multiple linear regression, adjusting for multiple potential confounders.

Results: After accounting for multiple testing and comparing homozygotes, tagSNPs in the type 1 angiotensin II receptor (AGTR1, rs6801836) and arachidonate 15-lipoxygenase (ALOX15, rs2664593) genes were each significantly (q < 0.2) associated with a 9-10% difference in the association between residential proximity to major roadways and LVM. Participants with suboptimal blood pressure control demonstrated stronger interactions between AGTR1 and traffic proximity.

Conclusions: Common polymorphisms in genes responsible for vascular function, inflammation, and oxidative stress appear to modify associations between proximity to major roadways and LVM. Further understanding of how genes modify effects of air pollution on CVD may help guide research efforts into specific mechanistic pathways.

Figure 1

Percent difference in LVM associated with living within 50 m of a major roadway compared with living > 150 m away (fully adjusted model), by all tagSNP homozygotes in ALOX15 (A) and AGTR1 (B). SNPs are arranged in their positional order along the chromosome. Data points indicate estimates for individuals homozygous for the minor allele (light blue) and for the major allele (dark blue). Numbers represent the number of participants in the significant genotype categories. Error bars are 95% CIs. *Interactions meeting q-value threshold for statistical significance (q < 0.2).

Figure 2

Race-stratified percent difference in LVM associated with living within 50 m of a major roadway compared with living > 150 m away (fully adjusted model) for tagSNPs showing significant evidence of interactive effects: rs2664593 in ALOX15 (A) and rs6801836 in AGTR1 (B). Error bars are 95% CIs.

Figure 3

Percent difference in LVM associated with living within 50 m of a major roadway compared with living > 150 m away, by blood pressure (BP) categories (optimal vs. suboptimal) according to JNC VII criteria and rs6801836 (AGTR1) genotype. Model comprises SNP, proximity to roadway categories, interaction terms between SNP and proximity, study site, age, sex, height, weight, principal components of AIMs, diabetes, lipids, education, income, alcohol use, physical activity, and smoking. Error bars are 95% CIs.