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

Publication ,  Journal Article
Asatryan, B; Shah, RA; Sharaf Dabbagh, G; Landstrom, AP; Darbar, D; Khanji, MY; Lopes, LR; van Duijvenboden, S; Muser, D; Lee, AM; Haggerty, CM ...
Published in: JACC Heart Fail
May 2024

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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Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

May 2024

Volume

12

Issue

5

Start / End Page

918 / 932

Location

United States

Related Subject Headings

  • United Kingdom
  • UK Biobank
  • Prognosis
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genetic Testing
  • Female
  • Exome Sequencing
 

Citation

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MLA
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Asatryan, B., Shah, R. A., Sharaf Dabbagh, G., Landstrom, A. P., Darbar, D., Khanji, M. Y., … Genotype-First Approach Investigators, . (2024). Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank. JACC Heart Fail, 12(5), 918–932. https://doi.org/10.1016/j.jchf.2023.07.023
Asatryan, Babken, Ravi A. Shah, Ghaith Sharaf Dabbagh, Andrew P. Landstrom, Dawood Darbar, Mohammed Y. Khanji, Luis R. Lopes, et al. “Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.JACC Heart Fail 12, no. 5 (May 2024): 918–32. https://doi.org/10.1016/j.jchf.2023.07.023.
Asatryan B, Shah RA, Sharaf Dabbagh G, Landstrom AP, Darbar D, Khanji MY, et al. Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank. JACC Heart Fail. 2024 May;12(5):918–32.
Asatryan, Babken, et al. “Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.JACC Heart Fail, vol. 12, no. 5, May 2024, pp. 918–32. Pubmed, doi:10.1016/j.jchf.2023.07.023.
Asatryan B, Shah RA, Sharaf Dabbagh G, Landstrom AP, Darbar D, Khanji MY, Lopes LR, van Duijvenboden S, Muser D, Lee AM, Haggerty CM, Arora P, Semsarian C, Reichlin T, Somers VK, Owens AT, Petersen SE, Deo R, Munroe PB, Aung N, Chahal CAA, Genotype-First Approach Investigators. Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank. JACC Heart Fail. 2024 May;12(5):918–932.
Journal cover image

Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

May 2024

Volume

12

Issue

5

Start / End Page

918 / 932

Location

United States

Related Subject Headings

  • United Kingdom
  • UK Biobank
  • Prognosis
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genetic Testing
  • Female
  • Exome Sequencing