Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.
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Jordan Elizabeth, Kinnamon Daniel D, Haas Garrie J, Hofmeyer Mark, Kransdorf Evan, Ewald Gregory A, Morris Alanna A, Owens Anjali, Lowes Brian, Stoller Douglas, Tang W H Wilson, Garg Sonia, Trachtenberg Barry H, Shah Palak, Pamboukian Salpy V, Sweitzer Nancy K, Wheeler Matthew T, Wilcox Jane E, Katz Stuart, Pan Stephen, Jimenez Javier, Fishbein Daniel P, Smart Frank, Wang Jessica, Gottlieb Stephen S, Judge Daniel P, Moore Charles K, Mead Jonathan O, Hurst Natalie, Cao Jinwen, Huggins Gordon S, Cowan Jason, Ni Hanyu, Rehm Heidi L, Jarvik Gail P, Vatta Matteo, Burke Wylie, Hershberger Ray E, DCM Precision Medicine Study of the DCM Consortium
Аннотация
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.