Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease

Abstract

There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic (“traffic exposure”)—a recognized vascular disease risk factor—on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10-8) in European-Americans. Rs755249 is located in the 3’ untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10-6) and rs1180341 (tibial artery, eQTL P = 5.3x10-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes.

A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic

“…Full details of the creation and use of this traffic exposure index in the CATHGEN cohort have been previously published [21] including in the context of a GWIS [24]. We defined major roadways as primary and secondary roadways.…”

“…Of these 2,100 genotyped individuals 1562 were European-American and 538 were African-American. These race-stratified cohorts and the quality control procedures have been previously described [24,32]. The quality control consisted of removing gender mismatches, variants with low (<98%) call frequency, individuals with a low (<98%) call rate, and related individuals.…”

“…Additionally, Eigenstrat-calculated principal components [35] were used to adjust for racial substructure within each of the race-specific GWIS. As in previous analyses four principal components were used for the EA subgroup; two principal components were sufficient to adjust for racial substructure in the AA subgroup [24,32]. The number of principal components was based on the adjustment necessary to remove racial substructure in previous race-stratified, genome-wide analyses in CATHGEN [24,32].…”

“…While these candidate gene studies have been informative, they lack the comprehensive assessment available in genome-wide interaction studies (GWIS). A recent GWIS for gene-air pollution interactions identified genetic variants in the bone morphogenic protein gene family associated with PAD [24]. A smoking exposure GWIS identified several novel genetic variants associated with coronary artery calcification; these include genetic variants in WWOX , which are also associated with PAD via an interactions with smoking and traffic air pollution exposure [24,25].…”

“…To identify novel genes associated with coronary atherosclerosis in a traffic exposure GWIS, we used the CATHeterization GENetics (CATHGEN) cohort [26], which has proven to be a successful approach to study both cardiovascular disease and environmental exposures [21,24,27,28]. For our analyses we utilized a race-stratified study design, and used distance from the primary residence to the nearest major roadway as a measure of traffic-related air pollution exposure (traffic exposure).…”