The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for ∼10%-15% of disease in non-African populations. The ∼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation. Unexpectedly, deleting the risk haplotype rescues VSMC stability, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This study shows that the risk haplotype selectively predisposes VSMCs to adopt a cell state associated with CAD phenotypes, defines new VSMC-based networks of CAD risk genes, and establishes haplotype-edited iPSCs as powerful tools for functionally annotating the human genome.

中文翻译：

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通过单倍型编辑揭示最有影响力的心血管风险源的作用。

9p21.3心血管疾病位点是冠状动脉疾病（CAD）最具影响力的常见遗传危险因素，在非非洲人群中约占疾病的10％-15％。约60 kb的风险单倍型是人特异性的，并且缺乏编码基因，从而阻碍了对其功能进行解读的努力。在这里，我们从风险和非风险个体中产生诱导性多能干细胞（iPSC），使用基因组编辑删除每个单倍型，并生成血管平滑肌细胞（VSMC）。风险VSMC的转录网络整体变化，与先前确定的CAD风险基因和途径相交，并伴有异常的粘附，收缩和增殖。出乎意料的是，删除风险单倍型可在表达9p21的同时拯救VSMC的稳定性。3相关的长非编码RNA ANRIL在非风险VSMC中诱导风险表型。这项研究表明，风险单倍型选择性地使VSMC倾向于采用与CAD表型相关的细胞状态，定义新的基于VSMC的CAD风险基因网络，并将单倍型编辑的iPSC建立为功能上注释人类基因组的强大工具。