Study Uncovers Genetic Basis for Heart Muscle Disease Common in Individuals of African Ancestry

Dilated cardiomyopathy (DCM), a leading cause of heart failure, is twice as common in Black individuals as in white individuals. This excess risk is not fully explained by known risk factors such as high blood pressure or socioeconomic barriers to care. Now, investigators from Mass General Brigham, the Broad Institute of MIT and Harvard, and VA Boston have identified a common gene variant that substantially increases DCM risk — a discovery made possible through large, ancestrally diverse biobanks. The findings, published in Nature Genetics, indicate that in individuals of African descent, this single mutation may be as important to DCM risk as hypertension.

“We’ve long known that individuals of self-identified Black race — and, presumably, African genetic ancestry — face a much higher risk of DCM, a disparity not explained fully by clinical or social factors. The drivers of this risk have remained elusive, but with the growth of large and diverse biobanks we’ve now uncovered a major genetic contributor,” said senior and corresponding author Krishna G. Aragam, MD, MS, who conducted this work while serving as a cardiologist at Mass General Brigham and a scientist at the Broad Institute of MIT and Harvard. Dr. Aragam now serves as the Director of Cardiovascular Genomics at the Cleveland Clinic.

The study used genetic information from over 95,000 participants of African genetic ancestry in the VA Million Veteran Program (MVP), including nearly 2,000 individuals with DCM. Through a genome-wide association study, designed to pinpoint slight differences between the DNA of those with and without DCM, the researchers determined that a one-letter change in the genetic code of the CD36 gene was associated with a 33% increase in risk of DCM. Individuals who inherited faulty copies of CD36 from both parents had nearly three-fold increased odds of DCM. 

CD36 encodes a protein that imports fatty acids into heart muscle cells — a critical fuel source for cardiac contraction. The specific CD36 gene variant linked to DCM was found in 17% of those with African ancestry, but less than 0.1% of those with European ancestry, a difference that the researchers speculate may be due to an association between the gene variant and malarial resistance.

“This is exactly why MVP was established — to include veterans from diverse backgrounds so we could identify important genetic drivers of disease that would otherwise be missed,” said J. Michael Gaziano, MD, MPH, founding principal investigator of MVP and a co-author of the study. “It’s remarkable that a gene variant this common and impactful could remain undiscovered for so long, and gratifying to see MVP helping to close that gap.”

The association between CD36 and DCM was validated in over 11,000 participants of African ancestry from the Penn Medicine Biobank. In three other cohorts with cardiac imaging data, the researchers found that carriers of the CD36 variant demonstrated evidence of impaired heart functioning even before manifesting symptoms of heart failure.

Overall, the researchers estimate that this single variant may account for approximately 20% of the excess risk of DCM observed in Black patients compared to white patients.

Laboratory experiments reinforced the mechanistic pathway: when researchers reduced CD36 expression in cultured heart muscle cells using RNA interference, the cells took up less fuel and showed impaired contraction.

“The CD36 story is fascinating because it connects a common genetic variant to fundamental questions of heart energetics,” said Patrick T. Ellinor, MD, PhD, co-senior author, executive director of the Mass General Brigham Heart and Vascular Institute and an institute member at the Broad. “It’s a striking example of how genetics can uncover mechanisms driving heart disease.”

The researchers are now exploring how CD36 compares to other genetic drivers of DCM, and whether targeting this pathway could help normalize cardiac energetics.

“Given its widespread impact in populations of African ancestry, we believe CD36 deserves to be part of clinical genetic testing for cardiomyopathy,” said Dr. Aragam. “And its biology points directly to the way the heart fuels itself, making it an especially compelling target for new therapies.”

Authorship: In addition to Aragam, Gaziano, and Ellinor, Mass General Brigham authors include Amil Shah and Jacob Joseph. Additional authors include Jennifer E. Huffman, Liam Gaziano, Zeina R. Al Sayed, Renae L. Judy, Laura M. Raffield, Kiran J. Biddinger, Brian Charest, Anant Chopra, David Gagnon, Xiuqing Guo, Vera Koledova, Michael G. Levin, Yuan-I Min, James P. Pirruccello, Nosheen Reza, Richard Ruan, Shefali S. Setia Verma, Bharath A. Venkatesh, Anurag Verma, Jie Yao, John J. Carr, Juan P. Casas, Kelly Cho, Joao A.C. Lima, Wendy S. Post, Daniel J. Rader, Marylyn D. Ritchie, Kent D. Taylor, James G. Terry, Stephen S. Rich, Christopher J. O'Donnell, Lawrence S. Phillips, Jerome I. Rotter, Peter W.F. Wilson, Yan V. Sun, and the VA Million Veteran Program.

Disclosures: O'Donnell is an employee of the Novartis Institute of Biomedical Research. Ellinor has received grant support from Bayer AG, Novo-Nordisk, Pfizer and Bristol Myers Squibb and has served on advisory boards for Bayer AG. Aragam has received grant support from Sarepta Therapeutics, Bayer AG, and Foresite Labs, and reports a research collaboration with the Novartis Institute for Biomedical Research. Gaziano has received institutional grant support from Novartis and Merck not related to the topic. No other relevant disclosures were reported for the remaining authors.

Funding: This study was funded in part by the Department of Veterans Affairs (I01CX001737, I01-BX004821, I01CX001922), the National Institutes of Health / National Heart, Lung, and Blood Institute (K08HL153937, 3U54HG003067-13S1, 3R01HL-117626-02S1, 3R01HL-120393-02S1, HHSN2682015000031/HSN26800004, 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, R01HL105756, R01HL160793, HHSN268201100037C, HHSN268201800002I, R01HL-120393, U01HL-120393, HHSN268201800001I, HHSN268201800013I, HHSN268201800014I, HHSN268201800015I, HHSN268201800010I, HHSN268201800011I, HHSN268201800012I), the National Institute on Minority Health and Health Disparities (HHSN268201800013I, HHSN268201800014I, HHSN268201800015I, HHSN268201800010I, HHSN268201800011I, HHSN268201800012I), and the American Heart Association (862032).

Paper cited: Huffman JE et al. “An African ancestry-specific nonsense variant in CD36 is associated with higher risk of dilated cardiomyopathy” Nature Genetics DOI: 10.1038/s41588-025-02372-2