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

Autor:	Park J; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Medicine, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York., Levin MG; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Zhang D; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Reza N; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Mead JO; Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus., Carruth ED; Department of Genomic Health, Geisinger, Danville, Pennsylvania., Kelly MA; Department of Genomic Health, Geisinger, Danville, Pennsylvania., Winters A; Autism and Developmental Medicine Institute, Geisinger, Danville, Pennsylvania., Kripke CM; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Judy RL; Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania., Damrauer SM; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania.; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Owens AT; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Bastarache L; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee., Verma A; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Kinnamon DD; Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus., Hershberger RE; Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.; Division of Cardiovascular Medicine, Department of Internal Medicine, and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus., Ritchie MD; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia., Rader DJ; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Jazyk:	angličtina
Zdroj:	JAMA cardiology [JAMA Cardiol] 2024 Nov 13. Date of Electronic Publication: 2024 Nov 13.
DOI:	10.1001/jamacardio.2024.3547
Abstrakt:	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.
Databáze:	MEDLINE
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