冠状动脉疾病风险变体rs6903956 通过PHACTR1法规与内皮功能障碍的联系
Kai Yi Tay1, Hannah Su-Ann Wee1, Nhi Nguyen1
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
bioRxiv : the preprint server for biology
|July 14, 2025
概括
像rs6903956这样的基因变异通过影响内皮细胞功能来影响冠状动脉疾病 (CAD) 风险. 这是一个很棒的节目,这是一个很棒的节目.
科学领域:
- 心血管遗传学 心血管遗传学
- 分子生物学分子生物学
- 内皮细胞生物学 内皮细胞生物学
背景情况:
- 缺血性心脏病,包括冠状动脉疾病 (CAD),是全球主要的健康问题.
- 单核酸多态 rs6903956 (染色体6p24.1) 与东亚人群中CAD易感性有关.
- 在CAD病变发生过程中,rs6903956的确切功能机制在很大程度上是未知的.
研究的目的:
- 阐明rs6903956在CAD病变发生过程中的机械作用,重点关注内皮细胞功能障碍.
- 研究RS6903956风险等位基因如何影响基因表达和内皮细胞炎症反应.
主要方法:
- 队列研究将rs6903956与血压和内皮反应 (流介导扩张) 联系起来.
- 在患者衍生的诱导多能干细胞-内皮细胞中单基编辑和表达量的特征位置分析.
- 在模型 (AlphaFold 3),功能测定 (促进剂活性),以及炎症标志物 (ICAM-1) 和单细胞粘附的评估.
主要成果:
- rs6903956"A"风险等位基因与改变的血压表型和减少的内皮反应相关.
- "A"等位基因对PHACTR1和EDN1表达产生cis作用的调节作用,与HOXA4/MEIS1转录因子的结合增强.
- rs6903956 "A"等位基因增加PHACTR1促进体活性,导致ICAM-1表达升高和在病理流下内皮细胞中的单细胞粘附.
结论:
- rs6903956通过HOX-MEIS合作结合影响PHACTR1表达,调节内皮细胞功能.
- 通过rs6903956对PHACTR1的基因特异调节有助于内皮功能障碍和增加CAD易感性.
- 这些发现提供了对心血管疾病遗传决定因素的机制性见解,并建议潜在的治疗点.
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