Aragam Krishna G, Chaffin Mark, Levinson Rebecca T, McDermott Gregory, Choi Seung Hoan, Shoemaker M Benjamin, Haas Mary E, Weng Lu-Chen, Lindsay Mark E, Smith J Gustav, Newton-Cheh Christopher, Roden Dan M, London Barry, Wells Quinn S, Ellinor Patrick T, Kathiresan Sekar, Lubitz Steven A
Center for Genomic Medicine (K.G.A., M.E.H., S.K.), Massachusetts General Hospital, Boston.
Cardiology Division and Cardiovascular Research Center (K.G.A., G.M., L.-C.W., M.E.L., C.N.-C., P.T.E., S.K., S.A.L.), Massachusetts General Hospital, Boston.
Circulation. 2019 Jan 22;139(4):489-501. doi: 10.1161/CIRCULATIONAHA.118.035774. Epub 2018 Nov 11.
Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery.
We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201).
We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (<1×10), the majority linked to upstream HF risk factors, ie, coronary artery disease ( and ) and atrial fibrillation (). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (, ). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; =3.62×10).
We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.
心力衰竭（HF）是一种发病机制和遗传机制尚未完全明确的遗传性疾病。因此，我们在一个大型国家生物样本库中研究了与HF相关的基因，并评估了细化的表型分类是否有助于基因发现。
我们在英国生物样本库的488010名参与者中定义了全因性HF，并进行了全基因组关联分析。我们通过将左心室功能障碍且无冠状动脉疾病的个体分类为患有非缺血性心肌病（NICM）来细化HF表型，并重复进行基因关联分析。然后，我们在独立队列中对主要的HF和NICM变异进行重复验证，并进行校正关联分析，以评估所确定的基因关联是否通过临床HF危险因素介导。此外，我们检测了24个已知扩张型心肌病基因中的罕见功能丧失突变与HF和NICM的关联。最后，我们使用心脏磁共振成像（n=4158）和超声心动图数据（n=30201）研究了无HF个体中主要变异与左心室结构和功能之间的关联。
我们在英国生物样本库中确定了7382名全因性HF参与者。全因性HF的全基因组关联分析确定了几个提示性位点（<1×10），大多数与上游HF危险因素相关，即冠状动脉疾病（和）和心房颤动（）。细化HF表型产生了2038例NICM病例的子集。与全因性HF不同，NICM的基因分析揭示了与扩张型心肌病相关的提示性位点（，）。我们的NICM分析产生的扩张型心肌病信号在独立队列中得到重复验证，在调整HF危险因素后仍然存在，并且与无临床HF个体的左心室功能障碍指标相关。此外，对功能丧失变异的分析表明是NICM的疾病易感基因（功能丧失变异携带者频率=0.01%；优势比，12.03；=3.62×10）。
我们在一个国家生物样本库中发现了全因性HF的几种不同遗传机制，这些机制反映了众所周知的HF危险因素。将表型细化为NICM亚型似乎有助于发现独立于临床HF危险因素且与亚临床左心室功能障碍相关的基因信号。
