Functional analysis of a common BAG3 allele associated with protection from heart failure

Multiple genetic association studies have correlated a common allelic block linked to the BAG3 gene with a decreased incidence of heart failure, but the molecular mechanism remains elusive. In this study, we used induced pluripotent stem cells to test if the only coding variant in this allele block, BAG3^C151R, alters protein and cellular function in human cardiomyocytes. Quantitative protein interaction analysis identified changes in BAG3^C151R protein partners specific to cardiomyocytes. Knockdown of genes encoding for BAG3-interacting factors in cardiomyocytes followed by myofibrillar analysis revealed that BAG3^C151R associates more strongly with proteins involved in the maintenance of myofibrillar integrity. Finally, we demonstrate that cardiomyocytes expressing the BAG3^C151R variant have improved response to proteotoxic stress in a dose-dependent manner. This study suggests that BAG3^C151R could be responsible for the cardioprotective effect of the haplotype block, by increasing cardiomyocyte protection from stress. Preferential binding partners of BAG3^C151R may reveal potential targets for cardioprotective therapies.