Background To investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we create a catalog of genetic variants associated with three stages of transcriptional cis -regulation in primary human coronary artery vascular smooth muscle cells (HCASMCs). Results We use a pooling approach with HCASMC lines to map regulatory variants that mediate binding of the CAD-associated transcription factor TCF21 with ChIPseq studies (bQTLs), variants that regulate chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with Hi-C methods (clQTLs). We examine the overlap of these QTLs and their relationship to smooth muscle-specific genes and transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlate to lead SNPs where they show allelic effects. By utilizing genome editing, we verify that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease-associated TGFB1-SMAD3 pathway to the CAD-associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping. Conclusions Together, these studies represent the most thorough mapping of multiple QTL types in a highly disease-relevant primary cultured cell type and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk.

中文翻译：

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使用数量性状基因座揭示 TCF21 结合、染色质可及性和染色体成环的冠状动脉疾病的分子机制

背景 为了研究冠状动脉疾病 (CAD) 风险的表观遗传和转录机制，以及染色质结构和功能的功能调节，我们创建了与原发性人类冠状动脉中转录顺式调节三个阶段相关的遗传变异目录血管平滑肌细胞 (HCASMCs)。结果 我们使用 HCASMC 系的汇集方法来绘制调节与 CAD 相关转录因子 TCF21 与 ChIPseq 研究 (bQTL) 结合的调节变体、通过 ATACseq 研究调节染色质可及性的变体 (caQTL) 以及使用 Hi-C 的染色体环化方法 (clQTL)。我们检查了这些 QTL 的重叠及其与平滑肌特异性基因和转录因子的关系。更多，我们使用多项分析来表明这些 QTL 与 CAD GWAS 基因座高度相关，并且与显示等位基因效应的先导 SNP 相关。通过利用基因组编辑，我们验证已识别的功能变异可以调节染色质可及性和染色体循环，为调节染色质状态和染色体结构的功能机制提供新的见解。最后，我们通过调节染色质可及性和染色体循环的响应 QTL 直接将疾病相关的 TGFB1-SMAD3 通路与 CAD 相关的 FN1 基因联系起来。结论一起，