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.

全基因组关联研究（Genome-wide association studies, GWAS）已鉴定出数百个与冠状动脉疾病（coronary artery disease, CAD）相关的遗传变异位点，但候选变异的调控机制仍未得到充分阐明。本研究借助转座酶可及性测序（Assay for Transposase Accessible Chromatin followed by sequencing, ATAC-seq）技术，对冠状动脉节段的表观基因组图谱进行了分析，探究了人类冠状动脉在健康状态与缺血性来源冠状动脉之间的染色质可及性差异，并阐明了如何通过染色质可及性解析CAD-GWAS结果的调控机制。本研究在人类冠状动脉样本中鉴定得到12226个对照特异性（Con）与1023个缺血特异性（Isc）差异可及区域（differentially accessible regions, DARs）。缺血性冠状动脉组织样本富集了免疫细胞激活相关的生物学通路，且约300个CAD相关遗传变异位点定位在DARs区域内。此外，我们还鉴定出可预测改变与CAD相关的转录因子结合位点的CAD关联变异。同时，我们在对照特异性DARs的邻近区域发现了内皮/平滑肌相关基因，在缺血特异性DARs的邻近区域发现了CAD相关基因。综上，本研究首次对健康及动脉粥样硬化性人类冠状动脉组织的染色质可及性进行了分析，通过调控动脉粥样硬化相关的顺式调控活性，对CAD-GWAS变异进行优先级排序以用于后续研究，并提出了可能影响CAD进展的调控机制假说。实验设计：我们对119名根据动脉粥样硬化疾病分期进行分组的患者的人类冠状动脉组织，构建并分析了ATAC-seq染色质可及性图谱。