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Variants in BAG3 Worsen Outcome in Dilated Cardiomyopathy Patients of African Ancestry

NEW YORK (GenomeWeb) – Genetic variants in the BAG3 gene that occur almost only in individuals with African ancestry contribute to a negative outcome in patients with dilated cardiomyopathy (DCM), according to a new study.

Led by researchers at Temple University and published in JAMA Cardiology today, the study focused on African-American patients with DCM and identified four genetic variants in BAG3 that were associated with an increase in cardiac events.

The results can potentially lead to new treatments, according to senior author Arthur Feldman, a professor of medicine at the Lewis Katz School of Medicine at Temple University. "BAG3 protein levels can potentially be restored in patients with loss of BAG3 alleles through gene therapy," he said in a statement.

Compared to other ethnic groups, African Americans are especially prone to heart failure related to DCM and to idiopathic dilated cardiomyopathy (IDC). Variants in a number of genes, among them BAG3, a conserved protein that is mostly expressed in the heart and skeletal muscle, have been linked to DCM, and previous studies suggested that BAG3 mutations may be particularly common in African Americans.

To find out whether BAG3 variants contribute to the prevalence or clinical outcomes of IDC in African Americans, the researchers sequenced the BAG3 gene in 509 African-American participants from three clinical trials: the Genetic Risk Assessment of African Americans with Heart Failure (GRAHF) study, the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2), and the Genetic Risk Assessment of Cardiac Events (GRACE) study.

They identified four BAG3 variants that were present in 42 of 402, or 10.4 percent, of individuals with nonischemic heart failure and in 9 of 107, or 8.4 percent, of patients with ischemic heart failure, as well as in African Americans without heart disease, but did not occur in a reference population of European ancestry.

Having one of those variants was associated with a nearly twofold increase in cardiac events, including death and heart failure-related hospitalization, compared to those who didn't carry them. "Thus, while they were not a disease-initiating factor, these variants were significantly associated with modified response to disease," the authors wrote.

The researchers also assessed the function of the four variants by expressing them in human ventricular myocytes and found that they increased apoptosis and decreased autophagy when the cells experienced hypoxia followed by reoxygenation. ClinVar, however, had classified the variants as either benign, likely benign, or of indeterminate pathogenicity, which the researchers wrote "emphasizes the lack of specificity of in silico pathogenicity prediction algorithms and the use of enhanced software and computational predictions in determining pathogenicity and providing annotation for [single nucleotide variants.]"

In addition, the variants had not been previously found in patient cohorts with familial DCM, probably due to the lack of African-American patients in genetic studies of heart failure. "The absence of racial/ethnic minority participants in genetic studies is an important disparity in cardiovascular research that needs to be addressed," the authors noted.