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

Abstract

Air pollution is a worldwide contributor to cardiovascular disease mortality and morbidity. Traffic-related air pollution is a widespread environmental exposure and is associated with multiple cardiovascular outcomes such as coronary atherosclerosis, peripheral arterial disease, and myocardial infarction. Despite the recognition of the importance of both genetic and environmental exposures to the pathogenesis of cardiovascular disease, studies of how these two contributors operate jointly are rare. We performed a genome-wide interaction study (GWIS) to examine gene-traffic exposure interactions associated with coronary atherosclerosis. Using race-stratified cohorts of 538 African-Americans (AA) and 1562 European-Americans (EA) from a cardiac catheterization cohort (CATHGEN), we identify gene-by-traffic exposure interactions associated with the number of significantly diseased coronary vessels as a measure of chronic atherosclerosis. We found five suggestive (P<1x10-5) interactions in the AA GWIS, of which two (rs1856746 and rs2791713) replicated in the EA cohort (P < 0.05). Both SNPs are in the PIGR-FCAMR locus and are eQTLs in lymphocytes. The protein products of both PIGR and FCAMR are implicated in inflammatory processes. In the EA GWIS, there were three suggestive interactions; none of these replicated in the AA GWIS. All three were intergenic; the most significant interaction was in a regulatory region associated with SAMSN1, a gene previously associated with atherosclerosis and B cell activation. In conclusion, we have uncovered several novel genes associated with coronary atherosclerosis in individuals chronically exposed to increased ambient concentrations of traffic air pollution. These genes point towards inflammatory pathways that may modify the effects of air pollution on cardiovascular disease risk.

Gene-by-environment interactions in urban populations modulate risk phenotypes

“…The four clinical traits that were found to be associated with differential gene expression (FEV1, lung disease, liver enzymes, and arterial stiffness), are consistently reported as influenced by air pollution by other studies 35 – 39 . Chronic diseases developing from these detrimental endophenotypes (asthma and cardiovascular diseases) are well documented to be associated with air pollution levels 12 – 14 , 22 , 37 . Gamma-glutamyltransferase (GGT) has been reported to occur in atherosclerotic plaques 40 , is elevated following pollution exposure 41 , 42 , and is predictive in a dose-dependent manner of cardiovascular risk 43 .…”

“…Environmental exposures, coupled with genetic variation, influence disease susceptibility, and deconstructing their respective contributions remains one of the principal challenges in understanding complex diseases 1 – 7 . Individuals with different genotypes may respond differently to environmental variation and generate an array of phenotypic landscape 8 – 14 . Such gene-by-environment interactions are thought to be pervasive and may be responsible for a large fraction of the unexplained variance in heritability and disease risk 9 , 15 , 16 .…”

A study on the mechanism of agonists in regulating transcriptional level of pIgR in salivary gland epithelial cells

“…The substances in the oral cavity should be cleared and excreted to keep the mouth relatively clean and sanitary, e.t.c. ( 2 , 3 ). As an important member of mucosal immune, polymeric immunoglobulin receptor (pIgR) is a member of immunoglobulin superfamily, and the only transporting receptor of polymeric immunoglobulin A (pIgA) and polymeric immunoglobulin M (pIgM).…”

Associations of urinary polymeric immunoglobulin receptor peptides in the context of cardio-renal syndrome

“…Due to the fact that pIgR/SC is not expressed in heart cells 15 , our findings point towards inflammatory pathways with respect to cardiovascular disease risk. A first hint in this direction was shown in a study where pIgR is associated with coronary atherosclerosis in coronary vessels of individuals chronically exposed to increased ambient concentrations of traffic air pollution 16 . In general, we showed with this study that the large collection of clinical and proteomics data available the Human Urinary Proteome Database can be of great use for the evaluation of specific urinary peptide levels under different disease conditions.…”