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首页> 外文期刊>PLoS Genetics >Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases
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Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases

机译：人血管细胞的基因组分析鉴定了<斜体> Twist1 作为常见血管疾病的因果基因

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Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2 , YAP1 , CFDP1 , and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1 . We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.
机译：基因组 - 宽协会研究已经确定了与血管疾病相关的多种新型基因组基因座。这些基因座中的许多是常见的非编码变体，其影响冠状动脉血管细胞内的疾病相关基因的表达。为了鉴定在基因组水平上的这种基因，我们对来自同一受试者的基因分型原发性人冠状动脉平滑肌细胞（HCAMCS）和冠状动脉内皮细胞（HCAECs）进行了深度转录组分析，包括剪接定量性状基因座（SQTL），等位基因特异性表达（ASE）和分层分析。我们鉴定了泌乳症和HCAECs中的Tars2，YAP1，CFDP1和STAT6的SQTL，以及233ASE基因，其子集也是动脉组织中的GTEX eGENes。 GWAS关联信号的冠状动脉疾病（CAD），偏头痛，中风和腹主动脉瘤中的冠状动脉和腹部主动脉瘤，冠状动脉和胫骨动脉患者为这些疾病发现了新的候选风险基因。在CAD和Stroke Locus标记为RS2107595，我们证明了具有近端基因Twist1的表达的分致化。我们表明，破坏RS2107595基因座改变了Twist1表达，并且风险等位基因具有增加的陷波信号蛋白RBPJ的结合。最后，我们提供Twist1表达影响血管SMC表型的数据，包括增殖和钙化，作为支持CAD中Twist1作用的潜在机制。

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