| Title: | Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank |
| Journal: | JACC Heart Failure |
| Published: | 2 Sep 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37715771/ |
| DOI: | https://doi.org/10.1016/j.jchf.2023.07.023 |
Publication 9648
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Abstract
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.</p>
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.</p>
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).</p>
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.</p>
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.</p>
22 Authors
- Babken Asatryan
- Ravi A. Shah
- Ghaith Sharaf Dabbagh
- Andrew P. Landstrom
- Dawood Darbar
- Mohammed Y. Khanji
- Luis R. Lopes
- Stefan van Duijvenboden
- Daniele Muser
- Aaron Mark Lee
- Christopher M. Haggerty
- Pankaj Arora
- Christopher Semsarian
- Tobias Reichlin
- Virend K. Somers
- Anjali T. Owens
- Steffen E. Petersen
- Rajat Deo
- Patricia B. Munroe
- Nay Aung
- C. Anwar A. Chahal
- Genotype-First Approach Investigators
1 Application
| Application ID | Title |
|---|---|
| 48286 | Do persons with epilepsy (PWE) have known pathogenic mutations in ion channel or other known sudden cardiac arrest-related genes at a greater frequency than non-epileptics? |
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