ImportanceThe genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM.ObjectiveTo interrogate the clinical traits and diseases associated with BAG3 coding variation.Design, Setting, and ParticipantsThis was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System’s clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study.ExposuresCarrier status for BAG3 coding variants.Main Outcomes and MeasuresAssociation of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes.ResultsIn PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358).Conclusions and RelevanceBAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

中文翻译：

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BAG3 中扩张型和肥厚型心肌病的双向风险调节剂和调节剂变体


重要性调节遗传性扩张型心肌病 （DCM） 外显率降低和可变表达性的遗传因素在很大程度上是未知的。BAG3 基因变异与 DCM 和肥厚型心肌病 （HCM） 有关，将 BAG3 指定为在 DCM 中携带潜在修饰变异的基因。设计、设置和参与者这是 Penn Medicine 生物银行 （PMBB） 的一项横断面研究，于 2014 年至 2023 年招募了宾夕法尼亚大学卫生系统临床实践站点的患者。全外显子组测序 （WES） 与电子健康记录 （EHR） 数据相关联，以将 BAG3 编码变异与 EHR 表型相关联。这是一项基于医疗保健人群的研究，包括 PMBB 中欧洲和非洲遗传血统的个体，WES 与 EHR 表型相关，在 BioVU、UK Biobank、MyCode 和 DCM 精准医学研究中进行了复制研究。主要结局和措施BAG3 编码变异与临床诊断、超声心动图特征和纵向结局的关联。结果在 PMBB （n = 43 731;中位 [IQR] 年龄，65 [50-76] 岁;21 907 名女性 [50.1%]）中，在 30 324 名欧洲人和 11 198 名非洲人中，常见的 C151R 变体与 DCM 风险降低 （比值比 [OR] ，0.85;95% CI，0.78-0.92） 和 HCM 风险同时增加相关 （OR，1.59;95% CI，1.25-2.02），这在复制队列中得到证实。根据死亡年龄评估，与非携带者相比，C151R 携带者的纵向结局有所改善（风险比 [HR]，0.85;95% CI，0.74-0.96;中位 [IQR] 年龄，携带者为 71.8 [63.1-80.7]，携带者为 70.3 [61.6-79]。2] 在非携带者中）和心脏移植（HR，0.81;95% CI，0.66-0.99;中位 [IQR] 年龄，携带者为 56.7 [46.1-63.1]，非携带者为 55.6 [45.2-62.9]）。C151R 与在心脏表达高外显 （n = 358） 中携带截短 TTN 变异的个体中 DCM （OR， 0.42;95% CI， 0.24-0.74） 和心力衰竭 （OR， 0.27;95% CI， 0.14-0.50） 的风险降低相关。结论和相关性BAG3 C151R 被确定为 DCM-HCM 谱上风险的双向调节因子，也是 TTN 介导的 DCM 中的重要遗传修饰因子变体。这项工作扩展了对 DCM 病因和外显率的理解，表明 BAG3 C151R 是一种重要的遗传修饰变体，有助于 DCM 的可变表达，值得进一步探索其机制和更广泛地研究 DCM 中的遗传修饰。