An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Jennifer E Huffman^#^{1

2}, Liam Gaziano^#^{1

3}, Zeina R Al Sayed^#³, Renae L Judy⁴, Laura M Raffield⁵, Kiran J Biddinger^{3

6}, Brian Charest¹, Anant Chopra⁷, David Gagnon^{1

8}, Xiuqing Guo⁹, Vera Koledova³, Michael G Levin⁴, Yuan-I Min¹⁰, James P Pirruccello¹¹, Nosheen Reza⁴, Richard Ruan³, Shefali Setia Verma^{12

13}, Bharath Ambale Venkatesh¹⁴, Anurag Verma^{12

13}, Jie Yao⁹, John Jeffrey Carr¹⁵, Juan P Casas¹⁶, Kelly Cho¹, Joao A C Lima¹⁴, Wendy S Post¹⁴, Daniel J Rader⁴, Marylyn D Ritchie⁴, Amil Shah¹⁷, Kent D Taylor⁹, James G Terry¹⁵, Stephen S Rich¹⁸, Christopher J O'Donnell¹⁶, Lawrence S Phillips¹⁹, Kathryn L Lunetta⁸, Jerome I Rotter⁹, Peter W F Wilson^{19

20}, J Michael Gaziano^{1

21}, Scott M Damrauer^{4

13}; VA Million Veteran Program; Yan V Sun^{20

22}, Patrick T Ellinor^{3

6}, Jacob Joseph^{23

24

25}, Krishna G Aragam^{26

27

28

29}

Collaborators, Affiliations

Collaborators

Affiliations

¹ VA Boston Healthcare System, Boston, MA, USA.
² VA Palo Alto Health Care System, Palo Alto, CA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁵ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Massachusetts General Hospital, Boston, MA, USA.
⁷ Bayer US, LLC, Cambridge, MA, USA.
⁸ Boston University School of Public Health, Boston, MA, USA.
⁹ The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ University of Mississippi Medical Center, Jackson, MS, USA.
¹¹ University of California San Francisco, San Francisco, CA, USA.
¹² University of Pennsylvania, Philadelphia, PA, USA.
¹³ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁴ Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
¹⁷ University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁸ University of Virginia, Charlottesville, VA, USA.
¹⁹ Emory University School of Medicine, Atlanta, GA, USA.
²⁰ Atlanta VA Medical Center, Decatur, GA, USA.
²¹ Brigham and Women's Hospital, Boston, MA, USA.
²² Emory University School of Public Health, Atlanta, GA, USA.
²³ VA Boston Healthcare System, Boston, MA, USA. jacob.joseph@va.gov.
²⁴ Brown University, Providence, RI, USA. jacob.joseph@va.gov.
²⁵ VA Providence Healthcare System, Providence, RI, USA. jacob.joseph@va.gov.
²⁶ VA Boston Healthcare System, Boston, MA, USA. karagam@broadinstitute.org.
²⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. karagam@broadinstitute.org.
²⁸ Massachusetts General Hospital, Boston, MA, USA. karagam@broadinstitute.org.
²⁹ Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA. karagam@broadinstitute.org.

^# Contributed equally.

PMID: 41174181
DOI: 10.1038/s41588-025-02372-2

An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Jennifer E Huffman et al. Nat Genet. 2025.

. 2025 Oct 31.

doi: 10.1038/s41588-025-02372-2. Online ahead of print.

Authors

Collaborators

Affiliations

¹ VA Boston Healthcare System, Boston, MA, USA.
² VA Palo Alto Health Care System, Palo Alto, CA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁵ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Massachusetts General Hospital, Boston, MA, USA.
⁷ Bayer US, LLC, Cambridge, MA, USA.
⁸ Boston University School of Public Health, Boston, MA, USA.
⁹ The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ University of Mississippi Medical Center, Jackson, MS, USA.
¹¹ University of California San Francisco, San Francisco, CA, USA.
¹² University of Pennsylvania, Philadelphia, PA, USA.
¹³ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁴ Johns Hopkins University, Baltimore, MD, USA.
¹⁵ Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
¹⁷ University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁸ University of Virginia, Charlottesville, VA, USA.
¹⁹ Emory University School of Medicine, Atlanta, GA, USA.
²⁰ Atlanta VA Medical Center, Decatur, GA, USA.
²¹ Brigham and Women's Hospital, Boston, MA, USA.
²² Emory University School of Public Health, Atlanta, GA, USA.
²³ VA Boston Healthcare System, Boston, MA, USA. jacob.joseph@va.gov.
²⁴ Brown University, Providence, RI, USA. jacob.joseph@va.gov.
²⁵ VA Providence Healthcare System, Providence, RI, USA. jacob.joseph@va.gov.
²⁶ VA Boston Healthcare System, Boston, MA, USA. karagam@broadinstitute.org.
²⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. karagam@broadinstitute.org.
²⁸ Massachusetts General Hospital, Boston, MA, USA. karagam@broadinstitute.org.
²⁹ Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA. karagam@broadinstitute.org.

^# Contributed equally.

PMID: 41174181
DOI: 10.1038/s41588-025-02372-2

Abstract

The high burden of dilated cardiomyopathy (DCM) in individuals of African descent remains incompletely explained. Here, to explore a genetic basis, we conducted a genome-wide association study in 1,802 DCM cases and 93,804 controls of African genetic ancestry (AFR). A nonsense variant ( rs3211938 :G) in CD36 was associated with increased risk of DCM. This variant, believed to be under positive selection due to a protective role in malaria resistance, is present in 17% of AFR individuals but <0.1% of European genetic ancestry (EUR) individuals. Homozygotes for the risk allele, who comprise ~1% of the AFR population, had approximately threefold higher odds of DCM. Among those without clinical cardiomyopathy, homozygotes exhibited an 8% absolute reduction in left ventricular ejection fraction. In AFR, the DCM population attributable fraction for the CD36 variant was 8.1%. This single variant accounted for approximately 20% of the excess DCM risk in individuals of AFR compared to those of EUR. Experiments in human induced pluripotent stem cell-derived cardiomyocytes demonstrated that CD36 loss of function impairs fatty acid uptake and disrupts cardiac metabolism and contractility. These findings implicate CD36 loss of function and suboptimal myocardial energetics as a prevalent cause of DCM in individuals of African descent.

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Conflict of interest statement

Competing interests: C.J.O. is an employee of the Novartis Institute of Biomedical Research. P.T.E. has received grant support from Bayer AG, Novo-Nordisk, Pfizer and Bristol Myers Squibb, and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. K.G.A. has received grant support from Sarepta Therapeutics, Bayer AG and Foresite Labs, and reports a research collaboration with the Novartis Institute for Biomedical Research. The other authors declare no competing interests.

References

1. McNally, E. M. & Mestroni, L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ. Res. 121, 731–748 (2017). - PubMed - PMC - DOI
1. Bibbins-Domingo, K. et al. Racial differences in incident heart failure among young adults. N. Engl. J. Med. 360, 1179–1190 (2009). - PubMed - PMC - DOI
1. Coughlin, S. S., Labenberg, J. R. & Tefft, M. C. Black–white differences in idiopathic dilated cardiomyopathy: the Washington DC dilated Cardiomyopathy Study. Epidemiology 4, 165–172 (1993). - PubMed - DOI
1. Chandra, A. et al. Race- and gender-based differences in cardiac structure and function and risk of heart failure. J. Am. Coll. Cardiol. 79, 355–368 (2022). - PubMed - PMC - DOI
1. Dries, D. L. et al. Racial differences in the outcome of left ventricular dysfunction. N. Engl. J. Med. 340, 609–616 (1999). - PubMed - DOI

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An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Collaborators

Affiliations

An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

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