Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank.

Asatryan, Babken; Shah, Ravi A; Sharaf Dabbagh, Ghaith; Landstrom, Andrew P; Darbar, Dawood; Khanji, Mohammed Y; Lopes, Luis R; van Duijvenboden, Stefan; Muser, Daniele; Lee, Aaron Mark; Haggerty, Christopher M; Arora, Pankaj; Semsarian, Christopher; Reichlin, Tobias; Somers, Virend K; Owens, Anjali T; Petersen, Steffen E; Deo, Rajat; Munroe, Patricia B; Aung, Nay; ... (2023). Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank. (In Press). JACC. Heart failure Elsevier 10.1016/j.jchf.2023.07.023

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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.

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