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

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

doi:10.1016/j.jchf.2023.07.023

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

JACC Heart Fail. 2023 Sep 2:S2213-1779(23)00492-4. doi: 10.1016/j.jchf.2023.07.023. Online ahead of print.

Authors

Babken Asatryan¹, Ravi A Shah², Ghaith Sharaf Dabbagh³, Andrew P Landstrom⁴, Dawood Darbar⁵, Mohammed Y Khanji⁶, Luis R Lopes⁷, Stefan van Duijvenboden⁸, Daniele Muser⁹, Aaron Mark Lee¹⁰, Christopher M Haggerty¹¹, Pankaj Arora¹², Christopher Semsarian¹³, Tobias Reichlin¹⁴, Virend K Somers¹⁵, Anjali T Owens¹⁶, Steffen E Petersen¹⁰, Rajat Deo¹⁶, Patricia B Munroe⁸, Nay Aung¹⁰, C Anwar A Chahal¹⁷; Genotype-First Approach Investigators

Affiliations

¹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK.
³ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania; University of Michigan, Division of Cardiovascular Medicine, Ann Arbor, Michigan.
⁴ Departments of Pediatrics, Division of Cardiology, and Cell Biology, Duke University School of Medicine, Durham, North Carolina.
⁵ University of Illinois, Chicago, Illinois.
⁶ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, West Smithfield, UK; NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London, UK; Newham University Hospital, Barts Health NHS Trust, London, UK.
⁷ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, West Smithfield, UK; Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
⁸ NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁹ Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Dipartimento Cardiotoracico, U.O.C. di Cardiologia, Presidio Ospedaliero Universitario "Santa Maria Della Misericordia," Udine, Italy.
¹⁰ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, West Smithfield, UK; NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.
¹¹ Department of Translational Data Science and Informatics, Geisinger, Danville, Pennsylvania.
¹² Division of Cardiovascular Disease, University of Alabama at Birmingham, Alabama.
¹³ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹⁴ Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁵ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.
¹⁶ Center for Inherited Cardiovascular Disease, Cardiovascular Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
¹⁷ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, West Smithfield, UK; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: chahal.anwar@mayo.edu.

PMID: 37715771
DOI: 10.1016/j.jchf.2023.07.023

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.

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.

Keywords: arrhythmogenic cardiomyopathy; cardiomyopathy; dilated cardiomyopathy; genetics; genotype-first approach; hypertrophic cardiomyopathy; sudden cardiac death.

Grants and funding

MR/T005181/1/MRC_/Medical Research Council/United Kingdom