Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 1;9(12):1124-1133.
doi: 10.1001/jamacardio.2024.3547.

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

Joseph Park  1   2   3   4 , Michael G Levin  2 , David Zhang  1   2   3 , Nosheen Reza  2 , Jonathan O Mead  5 , Eric D Carruth  6 , Melissa A Kelly  6 , Alex Winters  7 , Colleen M Kripke  1   3 , Renae L Judy  8 , Scott M Damrauer  1   8   9 , Anjali T Owens  2 , Lisa Bastarache  10 , Anurag Verma  1   3 , Daniel D Kinnamon  5 , Ray E Hershberger  5   11 , Marylyn D Ritchie  1   3 , Daniel J Rader  1   2   12
Affiliations

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

Joseph Park et al. JAMA Cardiol. .

Erratum in

  • Error in Results.
    [No authors listed] [No authors listed] JAMA Cardiol. 2025 Feb 26;10(4):402. doi: 10.1001/jamacardio.2025.0076. Online ahead of print. JAMA Cardiol. 2025. PMID: 40009404 Free PMC article. No abstract available.

Abstract

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 participants: This 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 measures: Association 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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Levin reported receiving funding to institution from Myome and grants from Doris Duke Foundation outside the submitted work. Dr Reza reported receiving speaker honoraria from Zoll; advisor fees from Roche Diagnostics and American Regent; and grants from Bristol Myers Squibb outside the submitted work. Dr Carruth reported receiving grants from the National Institutes of Health (R01HL141901) during the conduct of the study. Dr Kelly reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Winters reported receiving grants from the National Institutes of Health (R01 HL141901) during the conduct of the study. Dr Damrauer reported receiving grants from ReanlytixAI, nonfinancial support from Novo Nordisk, and consulting fees from Calico Labs outside the submitted work. Dr Owens reported receiving consulting fees from BMS, Alexion, Cytokinetics, Pfizer, Renovacor, BioMarin, Lexeo, Tenaya, Stealth, Edgewise, Imbria, and Corvista during the conduct of the study. Dr Bastarache reported receiving royalties from Nashville Biosciences outside the submitted work. Dr Kinnamon reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Hershberger reported receiving grants from the National Heart, Lung, and Blood Institute and BMS for a clinical trial outside the submitted work. Dr Ritchie reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

References

    1. Jordan E, Peterson L, Ai T, et al. Evidence-based assessment of genes in dilated cardiomyopathy. Circulation. 2021;144(1):7-19. doi: 10.1161/CIRCULATIONAHA.120.053033 - DOI - PMC - PubMed
    1. Maron BJ, Maron MS, Maron BA, Loscalzo J. Moving Beyond the sarcomere to explain heterogeneity in hypertrophic cardiomyopathy: JACC review topic of the week. J Am Coll Cardiol. 2019;73(15):1978-1986. doi: 10.1016/j.jacc.2019.01.061 - DOI - PMC - PubMed
    1. Shah RA, Asatryan B, Sharaf Dabbagh G, et al. ; Genotype-First Approach Investigators . Frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated putative pathogenic gene variants in UK Biobank participants. Circulation. 2022;146(2):110-124. doi: 10.1161/CIRCULATIONAHA.121.058143 - DOI - PMC - PubMed
    1. Schiabor Barrett KM, Cirulli ET, Bolze A, et al. Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation. Genet Med. 2023;25(4):100012. doi: 10.1016/j.gim.2023.100012 - DOI - PubMed
    1. Pirruccello JP, Bick A, Wang M, et al. Analysis of cardiac magnetic resonance imaging in 36 000 individuals yields genetic insights into dilated cardiomyopathy. Nat Commun. 2020;11(1):2254. doi: 10.1038/s41467-020-15823-7 - DOI - PMC - PubMed

Substances

LinkOut - more resources