Study Identifies Gene Variant That Increases Heart Failure Risk in People of African Ancestry

A new study has identified a common variant in the gene CD36, present in 17% of people with African ancestry, that substantially increases the risk of dilated cardiomyopathy, a leading cause of heart failure and heart transplantation.

The finding, published in Nature Genetics, uncovers a novel pathway for heart disease. Most known genetic causes of dilated cardiomyopathy damage the heart’s contractile machinery (its pumping system) directly.

However, the CD36 variant acts earlier in the process, disrupting how the heart takes up and converts certain types of fuels (long chain fatty acids) into energy. Over time, this energy shortfall weakens the heart muscle and ultimately leads to the same contractile dysfunction and heart failure seen in other forms of the disease.

The study was led by Krishna G. Aragam, M.D., the William E. Macaulay Endowed Chair in Cardiovascular Genomics and the Director of the Haslam-Bailey Family Section of Cardiovascular Genomics and Precision Medicine at Cleveland Clinic.

Dr. Aragam performed the research while at Mass General Brigham and the Broad Institute of MIT and Harvard. He is now conducting this work at Cleveland Clinic to accelerate translation from gene discovery to patient care.

“This discovery demonstrates the power of large-scale genomic and clinical data from diverse populations to identify high-impact and potentially actionable mechanisms of disease,” said Dr. Aragam. “By defining a pathway to dilated cardiomyopathy in which the heart’s ability to use fuel efficiently is impaired, we are laying the groundwork for new approaches to precision prevention and treatment of heart failure.”

This study also highlights how genomic research across a broad range of populations can uncover mechanisms that might otherwise remain undiscovered.

The study analyzed genetic data from over 95,000 participants of African ancestry in the VA Million Veteran Program (MVP), which included nearly 2,000 individuals with dilated cardiomyopathy. Through a genome-wide association analysis, the researchers identified a single-letter change in the CD36 gene linked to higher risk of dilated cardiomyopathy.

The CD36 variant occurs frequently in individuals of African ancestry but is virtually absent in those of European ancestry. Roughly 1 in 6 people of African descent carry one copy of the variant, which confers 33% higher risk of dilated cardiomyopathy; and 1 in 100 people of African ancestry carry two copies, which leads to a three-fold higher risk of developing dilated cardiomyopathy. 

The researchers found that in individuals of African descent, this single change contributes to more cases of dilated cardiomyopathy than diabetes -- one of the most common clinical risk factors for heart failure.

Furthermore, dilated cardiomyopathy is known to occur about twice as often in people of African ancestry compared with those of European ancestry, and this variant alone was estimated to account for roughly one-fifth of that long-observed difference in risk.

The discovery aligns with the mission of Cleveland Clinic’s newly established Section of Cardiovascular Genomics and Precision Medicine and Center for Cardiovascular Genomics and Data Sciences, which bring together clinical and research efforts to leverage genomic discoveries for cardiovascular care and to advance equity in cardiovascular health.

“Knowledge of this CD36 gene variant reframes how we think about unexplained cases of cardiomyopathy in some patients and opens the door to new approaches for evaluating and managing heart failure,” said Dr. Aragam. “Our work at Cleveland Clinic will now focus on translating these insights into meaningful advances for patients – from improving early heart failure detection to developing therapies that target this newly uncovered pathway.”