英国伦敦大学学院R. Thomas Lumbers团队发现，全基因组关联研究荟萃分析为心力衰竭及其亚型的病因学提供了见解。2025年3月4日出版的《自然—遗传学》杂志发表了这项成果。

在这项研究中，研究团队报告了一项190万人样本中HF及其亚型的全基因组关联研究。共有153174人患有HF，其中44012人患有非缺血性病因（ni-HF）。一组ni-HF患者根据左心室收缩功能分层，其中有数据可用，确定5406例射血分数降低，3841例射血分数保留。课题组确定了66个与HF及其亚型相关的遗传位点，其中37个以前未被报道过。

利用功能信息基因优先排序方法，课题组预测了每个鉴定位点的效应基因，并通过全表型关联分析、网络分析和共定位将这些基因映射到病因学疾病指标上。通过遗传富集分析，该课题组人员强调心外组织在疾病病因学中的作用。然后，小组研究上游危险因素与HF亚型的差异关联，主题为孟德尔随机化。这些发现扩展了他们对HF病因机制的理解，并可能为未来的预防和治疗方法提供信息。

据悉，心力衰竭（HF）是全球发病率和死亡率的主要原因。虽然不同的临床亚型，由病因和左心室射血分数定义，是公认的，他们的遗传决定因素仍然不充分了解。

附：英文原文

Title: Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes

Author: Henry, Albert, Mo, Xiaodong, Finan, Chris, Chaffin, Mark D., Speed, Doug, Issa, Hanane, Denaxas, Spiros, Ware, James S., Zheng, Sean L., Malarstig, Anders, Gratton, Jasmine, Bond, Isabelle, Roselli, Carolina, Miller, David, Chopade, Sandesh, Schmidt, A. Floriaan, Abner, Erik, Adams, Lance, Andersson, Charlotte, Aragam, Krishna G., rnlv, Johan, Asselin, Geraldine, Raja, Anna Axelsson, Backman, Joshua D., Bartz, Traci M., Biddinger, Kiran J., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunak, Sren, Bruun, Mie Topholm, Buckbinder, Leonard, Bundgaard, Henning, Carey, David J., Chasman, Daniel I., Chen, Xing, Cook, James P., Czuba, Tomasz, de Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Doney, Alexander S., Drr, Marcus, Dowsett, Joseph, Dudley, Samuel C., Engstrm, Gunnar, Erikstrup, Christian, Esko, Tnu, Farber-Eger, Eric H., Felix, Stephan B., Finer, Sarah, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Ghouse, Jonas, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan

Issue&Volume: 2025-03-04

Abstract: Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

DOI: 10.1038/s41588-024-02064-3

Source: https://www.nature.com/articles/s41588-024-02064-3