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Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry
Elizabeth Jordan1,2, Daniel D Kinnamon1,2, Garrie J Haas2,3
1Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus.
Insights
Black patients with dilated cardiomyopathy (DCM) have fewer actionable genetic variants than White patients due to genetic differences and underrepresentation in data. This impacts diagnosis and treatment strategies for diverse populations.
Area of Science:
- Genetics
- Cardiology
- Genomic Medicine
Background:
- Dilated cardiomyopathy (DCM) disproportionately affects Black patients, leading to worse outcomes.
- Existing genetic research for DCM is heavily biased towards White populations, limiting understanding of diverse genetic architectures.
- Genetic risk stratification and targeted therapies for DCM are hindered by this data gap.
Purpose of the Study:
- To investigate and compare the rare variant genetic architecture of DCM across different genomic ancestry groups.
- To identify ancestry-specific genetic factors contributing to DCM.
- To inform more equitable diagnostic and therapeutic approaches for DCM.
Main Methods:
- A cross-sectional study included 797 patients with DCM from diverse self-identified racial and ethnic groups (non-Hispanic Black, Hispanic, non-Hispanic White).
- Genetic variants in 36 DCM-associated genes were analyzed and classified by pathogenicity (pathogenic, likely pathogenic, uncertain significance).
- Comparison of variant frequencies and types was performed based on genomic ancestry, primarily African vs. European.
Main Results:
- Patients of African ancestry had a significantly lower percentage of clinically actionable variants compared to those of European ancestry (8.2% vs. 25.5%).
- This disparity was partly due to fewer loss-of-function variants in genes like TTN, but a higher number of uncertain significance missense variants in non-African ancestry specific genes.
- Limited published evidence supported the pathogenicity of variants found predominantly in patients of African ancestry.
Conclusions:
- The genetic architecture of DCM differs significantly between patients of African and European ancestry.
- Underrepresentation of African ancestry in genetic databases and clinical data limits the identification and interpretation of actionable DCM variants in these populations.
- Addressing these disparities is crucial for improving DCM diagnosis, risk prediction, and treatment for all patients.
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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