BAG3 Mutations Linked with Adverse Cardiovascular Outcomes

Mutations in unique Bcl2-associated anthanogene 3 (BAG3) functional genetic variants in individuals of African ancestry were associated with an increased risk for adverse cardiovascular outcomes, new study results suggest. 

Researchers for the multicohort study published online in JAMA Cardiology used DNA from African American individuals with dilated cardiomyopathy from three different clinical trials (the GRAHF, IMAC-2 and GRACE studies). The primary study endpoint included the prevalence of BAG3 mutations in African American individuals and event-free survival in those with functional BAG3 mutations.  

Genetic mutations in BAG3, a protein that regulates critical cellular processes in the heart and the skeletal muscle, increase the risk of death or worsening #heartfailure in individuals of African ancestry https://t.co/pjWirTRJ4r pic.twitter.com/t7rpfxQCny

— JAMA Cardiology (@JAMACardio) August 22, 2018

According to the results, four BAG3 mutations were identified and were expressed in populations of African descent, but not a reference population of individuals of European ancestry (P<0.001). Additionally, the presence of BAG3 variants was associated with a two-fold increase in the risk for adverse cardiovascular events (HR=1.97; 95% CI, 1.19 to 3.24]; P=0.01). 

“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 researchers wrote. “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.” 

Genetics in population health: Study shows genetic variants in BAG3 almost exclusively in African Americans = nearly 2-fold increase in cardiac events in carriers compared with noncarriers. https://t.co/bFojw8Dh30 https://t.co/TncdbomjrZ

— Charis Eng, MD, PhD (@CharisEngMDPhD) August 23, 2018

As @dgmacarthur has said so many times on Twitter and elsewhere ExAC (or gnomAD) is not a substitute for an appropriate control dataset. Here is a grave cautionary tale why. Thread by @skathire and others: https://t.co/TlPmbFrXxi

— Kasper Lage (@kasper_lage) August 23, 2018

Authors present a comparison of cumulative frequency of mutations in BAG3

in African Americans with cardiomyopathy
versus
that in whites in ExAC dataset

😳https://t.co/nImguIWEE1 pic.twitter.com/nG8lbUzh6l

— Sek Kathiresan MD (@skathire) August 22, 2018

Source: JAMA Cardiology