使用蛋白质学和孟德尔随机化确定心力衰竭的治疗点
Albert Henry1,2,3, María Gordillo-Marañón1,2, Chris Finan1,2,4
1Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom.
Circulation
|March 18, 2022
概括
这项研究确定了44种与心力衰竭 (HF) 相关的蛋白质,其中8种显示因果关系. 阿德伦米杜林成为治疗HF的一个有前途的治疗点.
科学领域:
- 心血管疾病研究
- 蛋白质组学和基因组学
- 药物发现和开发
背景情况:
- 心力衰竭 (HF) 是一种普遍的疾病,疾病机制尚不完全理解.
- 通过基因证据识别与疾病相关的蛋白质,可以发现HF的新治疗点.
研究的目的:
- 调查90种心血管蛋白和发生心力衰竭之间的观察和因果关系.
- 为潜在的HF疗法确定可用药物的蛋白质标.
主要方法:
- 对4项人群研究 (3019名参与者,732例HF事件) 的元分析,以评估蛋白质- HF相关性.
- 使用来自大型GWAS (> 30,000个体) 的cis蛋白质定量位置来确定因果关系的门德尔随机化.
- 多元敏感性分析和跨特征分析,以确保稳定性和探索机制.
主要成果:
- 在90种蛋白质中,有44种与发生性HF风险相关 (P<6. 0x10^-4).
- 8种蛋白质与HF有强烈的因果关系:CSF-1,Gal-3,KIM-1 (积极相关),ADM,CHI3L1,CTSL1,FGF-23,MMP-12 (具有保护性作用).
- 其中7种蛋白质是可用药的,ADM和Gal-3已经在临床试验中.
结论:
- 鉴定出44种与HF相关的循环蛋白,其中8种显示因果关系.
- 突出了7种可用药物的蛋白质,特别是上腺素 (ADM),作为HF的有前途的治疗点.
- 展示了一种整合基因组和蛋白质组数据的方法,以优先考虑复杂疾病的目标.
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