Abstract 17499: Genetic Variants in the Bone Morphogenic Protein (BMP) Family of Genes Interact with Mobile Source Air Pollution to Increase Risk of Peripheral Arterial Disease
Peripheral arterial disease (PAD) is a chronic disease affecting 12-15% of the general population and can cause pain, limb ischemia, and lead to amputation. Recent research has identified a role for both genetic variants in the etiology of PAD, and mobile source air pollution (MSAP) is strongly associated with PAD. However the joint risk of genetic variants and MSAP exposure has yet to be investigated. We used CATHGEN, a large cardiac catheterization cohort, to perform a GWAS investigating the role SNP-MSAP interactions have in increasing risk of PAD. We used race-stratified cohorts of 1647 whites (EA) and 546 blacks (AA) followed by meta-analysis to test for and replicate SNP-MSAP interactions associated with PAD. We used distance from recorded residence to the nearest roadway as a proxy for MSAP. A total of 905,956 SNPs were analyzed via logistic regression for each GWAS. We identified the 10 strongest SNP-MSAP interactions for each cohort and considered SNPs in introns, exons, or 3’-UTR regions of genes as signals of interest. The most significant SNP-MSAP interaction was for RS755249 located in the 3’-UTR of BMP8A (P = 8x10-7 EA, P = 0.4 AA, P= 2x10-6 meta-analysis). We saw concordance between the EA and AA cohorts with RS710913 in BMP8A (P = 5x10-5 EA, P = 0.03 AA, P = 4x10-6 meta-analysis). Given these results, we assessed association in other BMP genes and found interaction with a missense mutation in BMP2 among the whites (RS235768, P = 0.01). This SNP did not replicate in the blacks, but had a much lower minor allele frequency (MAF = 0.4 EA, 0.06 AA). We also observed interaction for another SNP in BMP2 that replicated at P < 0.05 (RS235764 - P = 0.03 EA, P = 0.004 AA, meta-analysis P = 0.001). Genes in the BMP family have been linked to vascular calcification and atherosclerosis, and exposure to black carbon, a by-product of diesel engine combustion, has been shown to cause a significant up-regulation of BMP2 in endothelial cells. These analyses identify several novel gene-environment interactions for PAD, and specifically suggest that genetic variants in BMP genes interact with MSAP to increase risk of PAD. Studies integrating gene expression and metabolic profiling are ongoing to more fully understand how genetic variants and MSAP exposure jointly increase risk of PAD.
- © 2012 by American Heart Association, Inc.