NYMC Faculty Publications

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry

Elizabeth Jordan, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Daniel D. Kinnamon, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Garrie J. Haas, Davis Heart and Lung Research Institute, The Ohio State University, Columbus.
Mark Hofmeyer, MedStar Health Research Institute, MedStar Washington Hospital Center, Washington, DC.
Evan Kransdorf, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Gregory A. Ewald, Washington University, St Louis, Missouri.
Alanna A. Morris, Emory University School of Medicine, Atlanta, Georgia.
Anjali Owens, Center for Inherited Cardiovascular Disease, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Brian Lowes, University of Nebraska Medical Center, Omaha.
Douglas Stoller, University of Nebraska Medical Center, Omaha.
W H. Tang, Cleveland Clinic, Cleveland, Ohio.
Sonia Garg, University of Texas Southwestern Medical Center, Dallas.
Barry H. Trachtenberg, Houston Methodist DeBakey Heart and Vascular Center, J. C. Walter Jr Transplant Center, Houston, Texas.
Palak Shah, Inova Heart and Vascular Institute, Falls Church, Virginia.
Salpy V. Pamboukian, University of Alabama, Birmingham.
Nancy K. Sweitzer, Sarver Heart Center, University of Arizona, Tucson.
Matthew T. Wheeler, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California.
Jane E. Wilcox, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Stuart Katz, New York University Langone Medical Center, New York, New York.
Stephen Pan, Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla.
Javier Jimenez, Miami Cardiac and Vascular Institute, Baptist Health South, Miami, Florida.
Daniel P. Fishbein, University of Washington, Seattle.
Frank Smart, Louisiana State University Health Sciences Center, New Orleans.
Jessica Wang, University of California Los Angeles Medical Center, Los Angeles.
Stephen S. Gottlieb, University of Maryland School of Medicine, Baltimore.
Daniel P. Judge, Medical University of South Carolina, Charleston.
Charles K. Moore, University of Mississippi Medical Center, Jackson.
Jonathan O. Mead, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Natalie Hurst, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Jinwen Cao, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Gordon S. Huggins, Cardiology Division, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts.
Jason Cowan, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.

Author Type(s)

Faculty

Journal Title

Jama

First Page

432

Last Page

441

Document Type

Article

Publication Date

8-1-2023

Department

Medicine

Abstract

IMPORTANCE: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. OBJECTIVE: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. DESIGN: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. EXPOSURE: Presence of DCM. MAIN OUTCOMES AND MEASURES: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). RESULTS: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). CONCLUSION AND RELEVANCE: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

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