在国家生物库中对心脏衰竭的表现精细化有助于基因发现
Krishna G Aragam1,2,3, Mark Chaffin3, Rebecca T Levinson4
1Center for Genomic Medicine (K.G.A., M.E.H., S.K.), Massachusetts General Hospital, Boston.
Circulation
|December 28, 2018
概括
在大型生物库中对心力衰竭 (HF) 的基因分析揭示了不同的机制. 将表型精制为非缺血性心肌病 (NICM) 便于发现独立于HF风险因素的遗传信号.
科学领域:
- 遗传学
- 心脏病学
- 生物银行
背景情况:
- 心力衰竭 (HF) 是一种复杂的遗传性疾病,其生物学机制尚不完全理解.
- 需要进行大规模的研究和精确的表型鉴定才能更好地发现HF的遗传关联.
研究的目的:
- 使用大型国家生物库调查与全因性心力衰竭 (HF) 的遗传关联.
- 评估将HF表型精制为非缺血性心肌病 (NICM) 是否可以改善遗传发现.
- 鉴定与HF和NICM相关的遗传变异及其与心脏结构和功能的关系.
主要方法:
- 对488010名英国生物库参与者进行全基因组关联分析 (GWAS).
- 对HF表型进行了细化,以识别2038例非缺血性心肌病 (NICM).
- 在独立的队列中进行复制,对风险因素进行调整的关联分析,并对扩张性心肌病基因的罕见功能丧失突变进行了测试.
主要成果:
- 在所有原因的GWAS中,确定了与已知的风险因素相关的位点,如冠状动脉疾病和心房动.
- 对NICM的基因分析显示,在扩大心肌病中存在暗示性位置,包括BAG3.
- 在BAG3中,功能丧失变异与NICM敏感性有显著的关联 (OR=12.03,P=3.62×10−5).
结论:
- 这种疾病的根源是不同的遗传机制,通常反映出已确定的风险因素.
- 对NICM的表型细化促进了独立于临床HF风险因素的遗传信号的发现.
- 鉴定出的基因变异与临床下左心室功能障碍有关,这表明它们在早期疾病发病过程中起作用.
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