Differential chromatin accessibility analysis elucidates mechanisms of coronary artery disease-associated genetic variation
Genome-wide association studies (GWAS) have identified hundreds of coronary artery disease (CAD) associated variants; however, the regulatory mechanisms for candidate variants remain mostly unknown. In this study, we evaluated the epigenomic landscape in coronary artery segments using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), addressed how chromatin accessibility in human coronary arteries differs from healthy vs ischemic heart derived-coronary arteries, and defined how chromatin accessibility can be used to understand mechanisms of CAD GWAS results. We report 12,226 control-specific (Con) and 1,023 Ischemic-specific (Isc) differentially accessible regions (DARs) in human coronary arteries. Isc tissue samples were enriched for immune cell activation and ~300 CAD-associated variants were mapped in DARs. We also identified CAD-associated variants predicted to alter transcripion factor binding sites related to CAD. Additionally, we identified  endothelial/smooth-muscle-associated genes proximal to Con-DARs and CAD-associated genes proximal to Isc-DARs. In summary, we provide an initial analysis of chromatin accessibility in heathy and atherosclerotic human coronary artery tissue, prioritizing CAD GWAS variants for downstream investigation by altering atherosclerosis-related cis-regulatory activity, and present hypotheses for regulatory mechanisms that could impact CAD progression. Overall design: We generated and analyzed ATAC-seq chromatin accessibility profiles in human coronary artery tissues from 119 patients stratified into categories based on atherosclerosis disease stages.