Background:Genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease (CAD). However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. Evidence suggests that the genetic influence on CAD susceptibility may act partly through vascular smooth muscle cells (VSMCs).Methods:We undertook genotyping, RNA sequencing, and cell behavior assays on a large bank of VSMCs (n>1499). Expression quantitative trait locus and splicing quantitative trait locus analyses were performed to identify genes with an expression that was influenced by CAD-associated variants. To identify candidate causal genes for CAD, we ascertained colocalizations of VSMC expression quantitative trait locus signals with CAD association signals by performing causal variants identification in associated regions analysis and the summary data–based mendelian randomization test. Druggability analysis was then performed on the candidate causal genes. CAD risk variants were tested for associations with VSMC proliferation, migration, and apoptosis. Collective effects of multiple CAD-associated variants on VSMC behavior were estimated by polygenic scores.Results:Approximately 60% of the known CAD-associated variants showed statistically significant expression quantitative trait locus or splicing quantitative trait locus effects in VSMCs. Colocalization analyses identified 84 genes with expression quantitative trait locus signals that significantly colocalized with CAD association signals, identifying them as candidate causal genes. Druggability analysis indicated that 38 of the candidate causal genes were druggable, and 13 had evidence of drug-gene interactions. Of the CAD-associated variants tested, 139 showed suggestive associations with VSMC proliferation, migration, or apoptosis. A polygenic score model explained up to 5.94% of variation in several VSMC behavior parameters, consistent with polygenic influences on VSMC behavior.Conclusions:This comprehensive analysis shows that a large percentage of CAD loci can modulate gene expression in VSMCs and influence VSMC behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets.

中文翻译：

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冠状动脉疾病相关变异对血管平滑肌细胞的影响

背景：全基因组关联研究已经确定了许多与冠状动脉疾病 (CAD) 密切相关的基因位点。然而，对于大多数这些位点，潜在的生物学机制仍然未知，阻碍了医学转化的进展。证据表明，遗传对 CAD 易感性的影响可能部分通过血管平滑肌细胞 (VSMC) 发挥作用。方法：我们对大量 VSMC (n>1499) 进行了基因分型、RNA 测序和细胞行为分析。进行表达数量性状基因座和剪接数量性状基因座分析，以鉴定具有受 CAD 相关变异影响的表达的基因。为了识别 CAD 的候选致病基因，我们通过在相关区域分析和基于摘要数据的孟德尔随机化测试中执行因果变异识别，确定了 VSMC 表达数量性状位点信号与 CAD 关联信号的共定位。然后对候选致病基因进行成药性分析。测试了 CAD 风险变异与 VSMC 增殖、迁移和凋亡的关联。通过多基因评分评估多个 CAD 相关变异对 VSMC 行为的集体影响。结果：大约 60% 的已知 CAD 相关变异在 VSMC 中表现出统计学上显着的表达数量性状基因座或剪接数量性状基因座效应。共定位分析确定了 84 个具有表达数量性状基因座信号的基因，这些基因与 CAD 关联信号显着共定位，将它们识别为候选因果基因。成药性分析表明，38 个候选致病基因是可成药的，13 个具有药物-基因相互作用的证据。在测试的 CAD 相关变体中，139 个显示出与 VSMC 增殖、迁移或凋亡的暗示关联。多基因评分模型解释了几个 VSMC 行为参数中高达 5.94% 的变异，这与多基因对 VSMC 行为的影响一致。结论：该综合分析表明，大部分 CAD 位点可以调节 VSMC 中的基因表达并影响 VSMC 行为。