Abstract Tu0086: Gene-Environment Interaction Between the <i>TRIP4</i> Locus and Air Pollution Exposure Increases Risk of Coronary Artery Disease

Introduction: Coronary artery disease (CAD) has a strong genetic component but known susceptibility loci only explain a fraction of its overall heritability. This observation suggests that other factors, such as gene-environment (GxE) interactions, can also contribute to CAD risk. In this regard, particulate matter &lt;2.5mM in diameter (PM 2.5 ) is one environmental pollutant that has consistently been associated with CAD. However, very few interactions between PM 2.5 exposure and genetic determinants of CAD have been identified. Hypothesis: We tested the hypothesis that risk of CAD could be mediated through GxE interactions between known susceptibility variants and PM 2.5 levels. Methods: Logistic regression was used to test 320 CAD loci for GxE interactions with PM 2.5 in the GeneBank and UK Biobank cohorts (total n=381,867). Expression quantitative trait locus (eQTL) data, in vitro transcriptomics profiling of human endothelial cells exposed to diesel exhaust or diesel exhaust particles (DEP) extract, and in vivo gene expression analyses of aortas from mice exposed to DEP or filtered air were used to prioritize positional candidate genes. Results: In the UK Biobank, CAD risk increased with a 2SD rise in PM 2.5 (OR=1.11, 95% CI 1.08-1.14; P=8.2x10 -13 ), NO 2 (OR=1.06, 95% CI 1.03-1.09; P=6.8x10 -5 ), and NO x (OR=1.07, 95% CI 1.04-1.10; P=7.4x10 -7 ). A GxE interaction was identified with a variant (rs6494488; A&gt;G) on chromosome 15 (P-int=1.2x10 -4 ). PM 2.5 exposure increased CAD risk more in AA homozygotes (OR=1.28, 95% CI 1.25-1.32; P=8.4x10 -60 ) than in AG heterozygotes (OR=1.17, 95% CI 1.11-1.23; P=1.4x10 -9 ) but not in GG homozygotes (OR=1.06, 95% CI 0.92-1.22; P=0.42). Of the genes at this locus, the A allele was only associated with lower TRIP4 mRNA in cardiometabolic tissues, with TRIP4 ~11% lower in CAD aortas than controls (P=2.7x10 -4 ). Human endothelial cells exposed to diesel exhaust or DEP extract in data sets showed reduced TRIP4 expression (P=2.8x10 -4 and P=0.02, respectively). Long-term exposure of mice to DEP decreased mRNA levels of Trip4 (P=5.9x10 -3 ) in the aorta but not any other positional candidate gene at the chromosome 15 locus. Conclusions: These results support the concept that risk of CAD can be influenced through interactions between genetic factors and air pollution exposure and suggest that one such GxE interaction at a chromosome 15 locus is potentially mediated by the athero-protective properties of TRIP4 at the level of the vessel wall.