冠状动脉疾病相关变体对血管光滑肌细胞的影响
Charles U Solomon1, David G McVey1, Catherine Andreadi1
1Department of Cardiovascular Sciences, University of Leicester, and National Institute for Health Research Leicester Biomedical Research Centre, UK (C.U.S., D.G.M., C.A., P.G., L.T., P.J.S., S.K., J.C.C., T.R.W., C.P.N., J.N.S., S.Y.).
Circulation
|June 23, 2022
概括
与冠状动脉疾病 (CAD) 相关的遗传变异会影响血管光滑肌细胞 (VSMC) 的基因表达. 这项研究确定了VSMC中可用药的基因是潜在的CAD治疗点.
科学领域:
- 遗传学
- 心血管生物学
- 药物基因组学
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了许多与冠状动脉疾病 (CAD) 相关的遗传位置.
- 大多数与CAD相关的位点背后的生物机制在很大程度上是未知的,阻碍了治疗转化.
- 对CAD的遗传倾向可能部分由血管光滑肌细胞 (VSMC) 介导.
研究的目的:
- 研究CAD相关基因变异在VSMC中调节基因表达和功能的作用.
- 通过将遗传关联数据与VSMC特异性表达量化特征位点 (eQTL) 整合来确定CAD的候选因果基因.
- 评估已识别的候选基因对于潜在的治疗开发的可用性.
主要方法:
- 在大量VSMC (n>1499) 上进行了基因定型,RNA测序和细胞行为测定.
- 进行了表达定量特征位 (eQTL) 和拼接定量特征位 (sQTL) 分析,以将CAD变异与基因表达变化联系起来.
- 包括因果变异鉴定和基于总结数据的门德尔随机化在内的局部化分析被用来确定候选因果基因.
- 用药性评估和多基因风险评分分析来评估治疗潜力和对VSMC行为的累积遗传影响.
主要成果:
- 大约60%的已知CAD相关变体在VSMC中表现出显著的eQTL或sQTL影响.
- 局部化分析确定了84个候选因果基因,其中eQTL信号与CAD关联信号重叠.
- 其中38个候选基因被认为是可用药的,其中13个具有药物基因相互作用的证据.
- 139个CAD风险变异与VSMC扩散,迁移或亡有关,多基因分数解释了VSMC行为变化的多达5. 94%.
结论:
- 大量的CAD基因位点会影响VSMC中的基因表达和行为.
- 已识别的可用药物的候选因果基因代表了CAD干预的有前途的治疗点.
- 这项研究弥合了基因发现和潜在的CAD治疗临床应用之间的差距.
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