Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes
Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes
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DOI：
10.1161/circresaha.122.321586
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发表时间：
2023-02-03
影响因子：
20.1
通讯作者：
Civelek, Mete
中科院分区：
文献类型：
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作者：
Aherrahrou, Redouane;Lue, Dillon;Civelek, Mete
背景：冠状动脉疾病（CAD）是全球范围内的首要致死病因。近期对全基因组关联研究的荟萃分析已确定了175多个与CAD相关的基因座。这些基因座大多位于非编码区域，据预测可调控基因表达。鉴于血管平滑肌细胞（SMCs）在CAD的发生发展过程中发挥关键作用，我们旨在找出与不同SMC表型中转录调控相关的CAD基因座子集。
方法：我们测量了151名不同遗传背景的心脏移植供体升主动脉中分离出的SMC在静止或增殖状态下的基因表达，并计算了其表达和剪接与全基因组中约630万个推算出的单核苷酸多态性标记之间的关联。
结果：我们确定了4910个表达数量性状基因座（eQTL）和4412个剪接数量性状基因座（sQTL），这些基因座代表了与转录本丰度和剪接相关的基因组区域。共有3660个eQTL在公开可用的基因型 - 组织表达数据集中未被发现。此外，分别有29个和880个eQTL具有SMC特异性和性别偏向性。我们将这些结果发布在一个用户友好的网站上供公众查询。为了确定由CAD基因座调控的效应转录本，我们采用了4种不同的共定位方法。我们确定了84个与CAD基因座共定位的eQTL和164个与CAD基因座共定位的sQTL，这突出了mRNA剪接的遗传调控作为CAD遗传风险分子机制的重要性。值得注意的是，20%的eQTL仅在静止的SMC中存在，35%的eQTL仅在增殖的SMC中存在。一个CAD基因座与一个性别特异性eQTL（TERF2IP）共定位，另一个基因座与SMC特异性eQTL（ALKBH8）共定位。关联性最为显著的CAD基因座9p21，是增殖性SMC中长链非编码RNA CDKN2B - AS1（也称为ANRIL）的sQTL。
结论：总体而言，我们的研究结果为不同SMC表型中CAD遗传易感性的分子机制提供了证据。
Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD loci associated with the regulation of transcription in distinct SMC phenotypes.Methods: We measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with similar to 6.3 million imputed single-nucleotide polymorphism markers across the genome.Results: We identified 4910 expression and 4412 splicing quantitative trait loci (sQTLs) representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait loci (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC-specific and sex-biased, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 sQTL that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with a sex-specific eQTL (TERF2IP), and another locus colocalized with SMC-specific eQTL (ALKBH8). The most significantly associated CAD locus, 9p21, was an sQTL for the long noncoding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs.Conclusions: Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes.