Common genetic variants help determine heart failure risk, study finds microbiologystudy

Screening for common genetic variants in addition to rare genetic variants can help improve patient risk stratification for heart failure, according to a recent study published in Nature Genetics led by investigators at Northwestern University Feinberg School of Medicine and the Perelman School of Medicine at the University of Pennsylvania.

“Much of the focus, at least on the clinical side, has been looking at rare genetic variants and testing for them and determining your heart failure risk. But based on our results, the common genetic variants in your genome can contribute just as much, if not more than, rare genetic variants to your heart failure risk,” said David Lee, MD, Ph.D., a resident physician in internal medicine at McGaw Medical Center of Northwestern University and lead author of the study.

Heart failure affects more than 60 million people worldwide, according to the World Heart Federation, and is the leading cause of unplanned hospitalizations in the United States for individuals 65 years and older.

Recent research efforts have aimed to identify common genetic variants, in addition to rare genetic variants, that may increase a person’s risk of heart failure. However, few studies have characterized how an individual’s unique combination of common and rare genetic variants might interact to influence their risk of heart failure.

“There’s been this open question of do these common genetic variants converge on similar pathways as rare genetic variants, or are they affecting completely different processes that might contribute to your individual heart failure risk?” Lee said.

In the study, Lee and his team performed a meta-analysis of genome-wide association studies that included genetic data from more than 207,000 individuals with heart failure and more than 2 million without heart failure.

This analysis ultimately revealed 176 new genetic variants that may contribute to heart failure risk, including coding variants in known cardiomyopathy genes (MYBPC3 and BAG3) and in regulators of lipoprotein, which helps transport lipids throughout the body, and glucose metabolism (GIPR and GLP1R).

The scientists also performed gene burden studies with data sourced from three biobanks, which included more than 27,000 individuals with heart failure and more than 349,000 without heart failure, and found exome-wide significant associations for heart failure and rare loss-of-function variants in the genes TTN, MYBPC3, FLNC and BAG3.

The findings underscore the value of identifying common genetic variants in addition to rare genetic variants when determining heart failure risk, Lee said.

“If you consider an individual’s common variant genetic background, we can identify individuals who are also at high risk for acquiring heart failure, even if they don’t have these rare genetic variants that typically are associated with high penetrance and causing disease. Our study shows that even for individuals who are carriers of these rare genetic variants, their common variant background can modify their risks,” Lee said.

The findings can also help identify different causal pathways that link increased risk of heart failure to other diseases, such as diabetes.

“Because we were able to identify so many common genetic variants that contribute to heart failure risk, we could cluster those and look across different diseases and find shared pathways between these diseases and heart failure to better understand the fundamental biological processes that are dysregulated in heart failure,” Lee said.

“The hope is that better understanding how these fundamental processes are altered at the genetic level may inform the development of future therapies that can be deployed in the clinic.”