Abstract 361: Epistasis Analysis Identifies Extracellular Matrix Genes Interacting With the COL4A1/COL4A2 Coronary Artery Disease Locus

Abstract

The COL4A1/COL4A2 locus on chromosome 13q34 was significantly associated with coronary artery disease (CAD) in the CARDIoGRAM (Nature Genetics, 2011) and the CARDIoGRAMPlusC4D (Nature Genetics, 2013) meta analyses of several large genome-wide association studies (GWAS). Determination of causative SNPs stemming from GWAS data requires a number of bioinformatic and lab based approaches. Functional analysis of GWAS loci can be aided by epistasis analysis, which interrogates synergistic associations with a given trait between pairs of SNPs, either at the same locus or at different loci. We investigated 4 CAD GWAS cohorts in this study (Ottawa Heart Genomics Study A, Ottawa Heart Genomics Study B, Cleveland Clinic Gene Bank, Duke CATHGEN Study). For epistasis analysis we tested whether CAD-associated SNPs at the COL4A1/COL4A2 locus displayed interaction with other CAD-associated SNPs across the genome and used 2 lists of SNPs. The first list of SNPs were ones at the COL4A1/COL4A2 locus significant for CAD association and the second list of SNPs were ones significantly associated with CAD from across the genome. Using PLINK we then generated a list of SNP pairs showing interaction (Pinteraction<0.05) for CAD association within 1 or more cohorts. Epistasis analysis generated over a dozen loci that demonstrated interaction with COL4A1/COL4A2 SNPs for CAD association, many of which have putative functional roles with respect to CAD. Genes integral to pathways involving COL4A1/COL4A2 were of particular interest in understanding the role of type IV collagen in CAD pathogenesis. We identified several extracellular matrix genes showing interaction with COL4A1/COL4A2 including fibronectin (FN1), COL18A1 as well as transmembrane proteins including ITGA2, encoding integrin α2 and SERPINF1, a member of the serpin peptidase family that strongly inhibits angiogenesis. Other interesting loci include NOTCH4, genes involved in angiogenesis, and mediators of TGFβ signalling. Functional studies are currently being conducted to decipher the roles of COL4A1/COL4A2 and these interacting extracellular matrix genes in CAD.