TY - JOUR
T1 - Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank
AU - Genotype-First Approach Investigators
AU - Asatryan, Babken
AU - Shah, Ravi A.
AU - Sharaf Dabbagh, Ghaith
AU - Landstrom, Andrew P.
AU - Darbar, Dawood
AU - Khanji, Mohammed Y.
AU - Lopes, Luis R.
AU - van Duijvenboden, Stefan
AU - Muser, Daniele
AU - Lee, Aaron Mark
AU - Haggerty, Christopher M.
AU - Arora, Pankaj
AU - Semsarian, Christopher
AU - Reichlin, Tobias
AU - Somers, Virend K.
AU - Owens, Anjali T.
AU - Petersen, Steffen E.
AU - Deo, Rajat
AU - Munroe, Patricia B.
AU - Aung, Nay
AU - Chahal, C. Anwar A.
N1 - Publisher Copyright:
© 2023 American College of Cardiology Foundation
PY - 2023
Y1 - 2023
N2 - Background: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population. Objectives: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank. Methods: Using whole exome sequencing data, variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). Results: Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (HR: 1.13 [95% CI: 1.01-1.25]; P = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR: 5.75 [95% CI: 4.58-7.23]; P < 0.0001), and elevated risk for composite outcome (HR: 1.29 [95% CI: 1.20-1.39]; P < 0.0001) than CMP-G− individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups. Conclusions: Adults with predicted deleterious variants in cardiomyopathy-associated genes exhibited a slightly higher risk of mortality and a significantly increased risk of developing cardiomyopathy, and cardiomyopathy-related composite outcomes, in comparison with genotype-negative controls.
AB - Background: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population. Objectives: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank. Methods: Using whole exome sequencing data, variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). Results: Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (HR: 1.13 [95% CI: 1.01-1.25]; P = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR: 5.75 [95% CI: 4.58-7.23]; P < 0.0001), and elevated risk for composite outcome (HR: 1.29 [95% CI: 1.20-1.39]; P < 0.0001) than CMP-G− individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups. Conclusions: Adults with predicted deleterious variants in cardiomyopathy-associated genes exhibited a slightly higher risk of mortality and a significantly increased risk of developing cardiomyopathy, and cardiomyopathy-related composite outcomes, in comparison with genotype-negative controls.
KW - arrhythmogenic cardiomyopathy
KW - cardiomyopathy
KW - dilated cardiomyopathy
KW - genetics
KW - genotype-first approach
KW - hypertrophic cardiomyopathy
KW - sudden cardiac death
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U2 - 10.1016/j.jchf.2023.07.023
DO - 10.1016/j.jchf.2023.07.023
M3 - Article
C2 - 37715771
AN - SCOPUS:85173154890
SN - 2213-1779
JO - JACC: Heart Failure
JF - JACC: Heart Failure
ER -