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Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals
Valerie D Myers1, Glenn S Gerhard2, Dennis M McNamara3
1Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Insights
Genetic variants in the Bcl2-associated anthanogene 3 (BAG3) gene, prevalent in individuals of African ancestry, are linked to poorer outcomes in dilated cardiomyopathy (DCM). These BAG3 variants do not cause DCM but worsen its prognosis by affecting cell function.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genomics and Precision Medicine
Background:
- Nonischemic dilated cardiomyopathy (DCM) disproportionately affects individuals of African ancestry compared to those of European ancestry.
- The genetic underpinnings of this disparity, particularly functional variants influencing outcomes, remain largely unexplored.
Purpose of the Study:
- To investigate the association between Bcl2-associated anthanogene 3 (BAG3) genetic variants and clinical outcomes in individuals of African ancestry with DCM.
- To explore the functional impact of identified BAG3 variants on cardiomyocyte apoptosis and autophagy.
Main Methods:
- A multicohort study utilizing DNA from African American individuals across three clinical studies (GRAHF, IMAC-2, GRACE) and heart transplant recipients.
- Genotyping for BAG3 variants and assessment of event-free survival in carriers versus non-carriers.
- In vitro studies involving transfection of human ventricular myocytes to evaluate the functional effects of BAG3 variants under hypoxic stress.
Main Results:
- Four BAG3 genetic variants were identified, present in 10.4% of African Americans with nonischemic heart failure and 8.4% with ischemic heart failure, and absent in a European ancestry reference population (P < .001).
- Carriers of BAG3 variants exhibited a nearly 2-fold increased risk of cardiac events (HR, 1.97; P = .01).
- In vitro, all four variants increased apoptosis and decreased autophagy in cardiomyocytes subjected to hypoxia-reoxygenation stress.
Conclusions:
- Genetic variants in BAG3, found predominantly in individuals of African ancestry, are associated with adverse outcomes in DCM patients.
- These variants modulate BAG3 function, impacting apoptosis and autophagy, thereby contributing to disease progression rather than causing the initial disease.
- The findings highlight the critical importance of considering biological diversity in genetic studies and understanding the functional impact of variants across different populations.
Importance:
The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants.
Objective:
We hypothesized that Bcl2-associated anthanogene 3 (BAG3) genetic variants were associated with outcomes in individuals of African ancestry with DCM.
Design:
This multicohort study of the BAG3 genotype in patients of African ancestry with dilated cardiomyopathy uses DNA obtained from African American individuals enrolled in 3 clinical studies: the Genetic Risk Assessment of African Americans With Heart Failure (GRAHF) study; the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2) study; and the Genetic Risk Assessment of Cardiac Events (GRACE) study. Samples of DNA were also acquired from the left ventricular myocardium of patients of African ancestry who underwent heart transplant at the University of Colorado and University of Pittsburgh.
Main Outcomes And Measures:
The primary end points were the prevalence of BAG3 mutations in African American individuals and event-free survival in participants harboring functional BAG3 mutations.
Results:
Four BAG3 genetic variants were identified; these were expressed in 42 of 402 African American individuals (10.4%) with nonischemic heart failure and 9 of 107 African American individuals (8.4%) with ischemic heart failure but were not present in a reference population of European ancestry (P < .001). The variants included 2 nonsynonymous single-nucleotide variants; 1 three-nucleotide in-frame insertion; and 2 single-nucleotide variants that were linked in cis. The presence of BAG3 variants was associated with a nearly 2-fold (hazard ratio, 1.97 [95% CI, 1.19-3.24]; P = .01) increase in cardiac events in carriers compared with noncarriers. Transfection of transformed adult human ventricular myocytes with plasmids expressing the 4 variants demonstrated that each variant caused an increase in apoptosis and a decrease in autophagy when samples were subjected to the stress of hypoxia-reoxygenation.
Conclusions And Relevance:
This study demonstrates that genetic variants in BAG3 found almost exclusively in individuals of African ancestry were not causative of disease but were associated with a negative outcome in patients with a dilated cardiomyopathy through modulation of the function of BAG3. The results emphasize the importance of biological differences in causing phenotypic variance across diverse patient populations, the need to include diverse populations in genetic cohorts, and the importance of determining the pathogenicity of genetic variants.
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