Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3

被引：1

作者：

Park, Joseph ^{[1
,2
,3
,4
]}

Levin, Michael G. ^{[2
]}

Zhang, David ^{[1
,2
,3
]}

Reza, Nosheen ^{[2
]}

Mead, Jonathan O. ^{[5
]}

Carruth, Eric D. ^{[6
]}

Kelly, Melissa A. ^{[6
]}

Winters, Alex ^{[7
]}

Kripke, Colleen M. ^{[1
,3
]}

Judy, Renae L. ^{[8
]}

Damrauer, Scott M. ^{[1
,8
,9
]}

Owens, Anjali T. ^{[2
]}

Bastarache, Lisa ^{[10
]}

Verma, Anurag ^{[1
,3
]}

Kinnamon, Daniel D. ^{[5
]}

Hershberger, Ray E. ^{[5
,11
,12
]}

Ritchie, Marylyn D. ^{[1
,3
]}

Rader, Daniel J. ^{[1
,2
,13
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Genet, 11-125 Smilow Ctr Translat Res,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Inst Biomed Informat, Philadelphia, PA 19104 USA

[4] Weill Cornell Med, NewYork Presbyterian Hosp, Dept Med, New York, NY USA

[5] Ohio State Univ, Dept Internal Med, Div Human Genet, Columbus, OH USA

[6] Geisinger, Dept Genom Hlth, Danville, PA USA

[7] Geisinger, Autism & Dev Med Inst, Danville, PA USA

[8] Corporal Michael Crescenz VA Med Ctr, Dept Surg, Philadelphia, PA 19104 USA

[9] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA

[10] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[11] Ohio State Univ, Dept Internal Med, Div Cardiovasc Med, Columbus, OH USA

[12] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH USA

[13] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

来源：

JAMA CARDIOLOGY | 2024年 / 9卷 / 12期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; HEART-FAILURE; BIOBANK;

D O I：

10.1001/jamacardio.2024.3547

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Importance The 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. Objective To 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. Exposures Carrier status for BAG3 coding variants. Main Outcomes and MeasuresAssociation of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. Results In 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 Relevance BAG3 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.

引用

页码：1124 / 1133

页数：10