Background:Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported.Methods:Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts.Results:A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P=3.10×10⁻⁸) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=−0.83 and P=8.24×10⁻¹⁷). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at TMEM40 or BAG3 on EF are largely independent of these conditions.Conclusions:In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3, associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

中文翻译：

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对 26 638 名个体的荟萃分析确定了与左心室射血分数相关的两个遗传位点。

背景：左心室射血分数 (EF) 是心脏功能的指标，通常在患有心力衰竭和其他心脏病的个体中进行评估。尽管家族研究表明 EF 具有重要的遗传成分，其遗传力估计值高达 0.61，但迄今为止仅报道了 6 个 EF 相关位点。从遗传流行病学研究成人健康与老龄化和英国生物银行cohorts.Results成人：一项荟萃分析，从遗传流行病学研究成人保健相结合的结果与老龄化和英国生物银行确定了新的轨迹：TMEM40染色体3p25（rs11719526;β =0.47 且P =3.10×10 ^-8) 在日本生物银行复制并证实了最近的发现，即 EF 变异中染色体 10q26 上的BAG3基因座，观察到的最强关联 rs17617337 (β=-0.83 和P =8.24×10 ^-17 )。尽管TMEM40 rs11719526的次要等位基因频率在不同种族群体中普遍普遍（在 0.13 和 0.44 之间），但BAG3rs17617337 在亚洲和非洲血统人群中很少见（次要等位基因频率<0.05）。考虑到先前的心脏病（即心力衰竭/心肌病、高血压、心肌梗塞、心房颤动、瓣膜疾病和血运重建手术）后，这些关联略有减弱。这表明TMEM40或BAG3的先导变异对 EF 的影响在很大程度上独立于这些条件。 结论：在这项大型多种族研究中，我们确定了 2 个基因座，TMEM40和BAG3，在全基因组显着性水平上与 EF 相关。识别和理解 EF 的遗传决定因素对于更好地理解这种与心脏结果强相关的病理生理学以及帮助确定未来疗法的发展非常重要。