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Association of Pathogenic/Likely Pathogenic Genetic Variants for Cardiomyopathies With Clinical Outcomes : A Multiancestry Analysis in the All of Us Research Program

Shetty, Naman S. ; Pampana, Akhil ; Gaonkar, Mokshad ; Patel, Nirav ; Vekariya, Nehal ; Smith, J. Gustav LU orcid ; Kalra, Rajat ; Chahal, C. Anwar A. ; Semsarian, Christopher and Li, Peng , et al. (2025) In Circulation: Genomic and Precision Medicine 18(3).
Abstract

BACKGROUND: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. METHODS: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic... (More)

BACKGROUND: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. METHODS: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group. RESULTS: Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% in the overall population and 0.8%, 0.8%, 0.5%, and 1.2% among European, African, East Asian, and South Asian ancestry individuals, respectively. Over their lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (adjusted hazard ratio, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (adjusted hazard ratio, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (adjusted hazard ratio, 2.12 [95% CI, 1.78-2.53]). CONCLUSIONS: Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
arrhythmias, cardiomyopathies, genetics, heart failure
in
Circulation: Genomic and Precision Medicine
volume
18
issue
3
article number
e005113
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:40433684
  • scopus:105007091748
ISSN
2574-8300
DOI
10.1161/CIRCGEN.124.005113
language
English
LU publication?
yes
id
597e775d-0697-4630-bb9d-6c4576ab7c82
date added to LUP
2025-09-26 12:30:18
date last changed
2025-09-26 14:54:20
@article{597e775d-0697-4630-bb9d-6c4576ab7c82,
  abstract     = {{<p>BACKGROUND: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. METHODS: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group. RESULTS: Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% in the overall population and 0.8%, 0.8%, 0.5%, and 1.2% among European, African, East Asian, and South Asian ancestry individuals, respectively. Over their lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (adjusted hazard ratio, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (adjusted hazard ratio, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (adjusted hazard ratio, 2.12 [95% CI, 1.78-2.53]). CONCLUSIONS: Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.</p>}},
  author       = {{Shetty, Naman S. and Pampana, Akhil and Gaonkar, Mokshad and Patel, Nirav and Vekariya, Nehal and Smith, J. Gustav and Kalra, Rajat and Chahal, C. Anwar A. and Semsarian, Christopher and Li, Peng and Arora, Garima and Arora, Pankaj}},
  issn         = {{2574-8300}},
  keywords     = {{arrhythmias; cardiomyopathies; genetics; heart failure}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Circulation: Genomic and Precision Medicine}},
  title        = {{Association of Pathogenic/Likely Pathogenic Genetic Variants for Cardiomyopathies With Clinical Outcomes : A Multiancestry Analysis in the All of Us Research Program}},
  url          = {{http://dx.doi.org/10.1161/CIRCGEN.124.005113}},
  doi          = {{10.1161/CIRCGEN.124.005113}},
  volume       = {{18}},
  year         = {{2025}},
}