: Publication 14667

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.

14 Keywords

Adaptor Proteins, Signal Transducing
Aged
Apoptosis Regulatory Proteins
Cardiomyopathy, Dilated
Cardiomyopathy, Hypertrophic
Cross-Sectional Studies
Echocardiography
Exome Sequencing
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Phenotype

18 Authors

Joseph Park
Michael G. Levin
David Zhang
Nosheen Reza
Jonathan O. Mead
Eric D. Carruth
Melissa A. Kelly
Alex Winters
Colleen M. Kripke
Renae L. Judy
Scott M. Damrauer
Anjali T. Owens
Lisa Bastarache
Anurag Verma
Daniel D. Kinnamon
Ray E. Hershberger
Marylyn D. Ritchie
Daniel J. Rader

1 Application

Application ID	Title
32133	Integration of multi-organ imaging phenotypes, clinical phenotypes, and genomic data

Title:	Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3
Journal:	JAMA Cardiology
Published:	1 Dec 2024
Pubmed:	https://pubmed.ncbi.nlm.nih.gov/39535783/
DOI:	https://doi.org/10.1001/jamacardio.2024.3547