In newly published research, researchers identify a genetic variant in the BAG3 gene that they think plays a complex, dual role in the risk spectrum of dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Led by Joseph Park, MD, PhD, from the University of Pennsylvania Perelman School of Medicine, Philadelphia, the study’s focus centers on the BAG3 C151R variant that the team associate with a decreased risk for DCM. Simultaneously, the C151R variant is also associated with an increased risk for hypertrophic cardiomyopathy (HCM). “Our findings suggest that C151R serves as a bidirectional modulator of risk in the paradigm of DCM and its outcomes, as well as a role as a dial modulating the extent of protection from DCM vs predisposition to HCM,” said the authors of the paper, published in JAMA Cardiology on Wednesday. “Our study provides both diagnostic and echocardiographic evidence that DCM and HCM occur along a spectrum." Whole-exome sequencing The study, which spanned nine years, recruited over 43,000 patients where the team utilized whole-exome sequencing that was linked to electronic health records (EHR). Results revealed that the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% confidence interval [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). The assessment extended to those who received a 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 also 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 titin (TTN) gene variants in exons with high cardiac expression (n=358). Specifically, C151R carriers were 15% less likely to develop DCM but exhibited a 59% greater risk for HCM. Findings summary In summary, the results suggested that the C151R variant in BAG3 was associated with a 15% decrease in DCM risk and a 59% increase in HCM risk among carriers. For carriers with TTN truncating variants, the C151R variant reduced the likelihood of DCM by 48%. C151R carriers with DCM also showed improved outcomes, including a 15% reduction in mortality risk and a 19% decrease in heart transplant likelihood compared to non-carriers. The authors suggested that in order to improve risk assessment among titin‐truncating variant (TTNtv) carriers, additional studies and meta-analyses in health care populations were needed.“We suggest that this common (MAF >20% in Ashkenazi Jewish individuals, Europeans, and South Asian individuals; MAF approximately 13% in Latino and Middle Eastern individuals; MAF = 3.7% in African individuals) variant could be included in such a panel for counseling patients with pathogenic TTNtvs. “[This would be] to help clarify other genetic factors which may modify predisposition to ultimately developing DCM.” BAG3 variant role Despite the implications of the study outcomes, the authors acknowledged a number of constraints in their study. Chief amongst them was the lack of statistical power to explore the influence of C151R across all possible genetic backgrounds and in various DCM etiologies beyond TTN truncating variants. While significant, the study’s conclusions about C151R’s protective effect on DCM was limited to a cross-sectional analysis, in which the team recommended the introduction of longitudinal studies to reinforce the findings. To extend this theme, the team also called for larger and more comprehensive genetic studies to confirm BAG3 C151R's effects on DCM and HCM across diverse populations and to examine additional potential genetic modifiers of DCM risk. Study design The cross-sectional study included individuals from the Penn Medicine BioBank (PMBB) with whole-exome sequencing (WES) linked to electronic health record (EHR) phenotypes. In addition, replication studies in BioVU, UK Biobank, MyCode and DCM Precision Medicine Study were included.The study’s main outcome was the association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. Source: Park J, Levin MG, Zhang D, et al. Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3. JAMA Cardiol. (Article in press). Image Credit: PatinyaS. – stock.adobe.com