冠状动脉疾病风险位置通过MTAP的增强驱动调节来调节血管细胞状态过渡
Timothy N Audam1,2,3, Benjamin Schmandt1,2,3, Yi Huang1,2
1Medical and Population Genetics Program, Cardiovascular Disease Initiative, & Broad Diabetes Initiative, Broad Institute of MIT and Harvard, Cambridge, MA.
bioRxiv : the preprint server for biology
|December 3, 2025
概括
9p21.3位点与冠状动脉疾病 (CAD) 有着强烈的关联. 应激反应性血管细胞和由增强剂调节的MTAP基因与CAD病理生理学有关.
科学领域:
- 遗传学 是一个遗传学.
- 心血管生物学 心血管生物学
- 分子生物学分子生物学
背景情况:
- 9p21.3位点是冠状动脉疾病 (CAD) 最重要的遗传风险因素.
- 这种关联背后的精确分子机制在很大程度上是未知的.
- 了解9p21.3中的调节元件和效应基因对于阐明CAD病变的发病过程至关重要.
研究的目的:
- 绘制血管细胞中9p21.3位点的调节结构.
- 确定导致CAD风险的特定基因和变异.
- 研究9p21.3基因变异对血管细胞行为的功能后果.
主要方法:
- 在纤维细胞和光滑肌细胞中的9p21.3 CAD风险单元型内的增强剂的映射.
- 克里斯普尔干扰 (CRISPRi) 划分,精细映射和基因组约束分析在一个大队列 (>500,000个人) 中.
- 干扰和多模分析,以评估MTAP基因调制的功能影响.
主要成果:
- 在9p21.3 CAD风险单元型中确定了12种应激反应增强剂.
- 指定MTAP作为可能的效应基因和rs1537371作为潜在的因果变异.
- 证明MTAP损失促进亲纤维和血管新生通路,使血管细胞对TGF-β诱导的变化敏感.
结论:
- 在9p21.3的非编码变异通过作用于MTAP的血管特异增强器网络调节CAD风险.
- MTAP是以前未知的血管重塑的调节器,将9p21.3遗传风险与细胞病理联系起来.
- 由MTAP介导的血管壁细胞的压力诱导的变化与冠状动脉疾病的发展有关.
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