Normal view MARC view ISBD view

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

MedStar author(s):

Citation: JAMA. 330(5):432-441, 2023 08 01.PMID: 37526719Institution: MedStar Heart & Vascular InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., ExtramuralSubject headings: *American Indian or Alaska Native | *Black People | *Cardiomyopathy, Dilated | *Hispanic or Latino | *White People | American Indian or Alaska Native/ge [Genetics] | Black People/ge [Genetics] | Cardiomyopathy, Dilated/eh [Ethnology] | Cardiomyopathy, Dilated/ge [Genetics] | Cross-Sectional Studies | Genomics | Hispanic or Latino/ge [Genetics] | Humans | White People/ge [Genetics]Year: 2023 Local holdings: Available online from MWHC library: 1998 - present, Available in print through MWHC library: 1999 - presentISSN:

0098-7484

Name of journal: JAMAAbstract: 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.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.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.Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.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).All authors: Burke W, Cao J, Cowan J, Ewald GA, Fishbein DP, Garg S, Gottlieb SS, Haas GJ, Hershberger RE, Hofmeyer M, Huggins GS, Hurst N, Jarvik GP, Jimenez J, Jordan E, Judge DP, Katz S, Kinnamon DD, Kransdorf E, Lowes B, Mead JO, Moore CK, Morris AA, Ni H, Owens A, Pamboukian SV, Pan S, Rehm HL, Shah P, Smart F, Stoller D, Sweitzer NK, Tang WHW, Trachtenberg BH, Vatta M, Wang J, Wheeler MT, Wilcox JEFiscal year: FY2024 Digital Object Identifier:

https://dx.doi.org/10.1001/jama.2023.11970

Date added to catalog: 2023-10-04

Holdings ( 1 )
Title notes ( 9 )

Holdings
Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	37526719	Available		37526719

Available online from MWHC library: 1998 - present, Available in print through MWHC library: 1999 - present

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.

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.

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.

Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).

Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.

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).

English