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
; 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.
(Less)
- author
- Shetty, Naman S.
; Pampana, Akhil
; Gaonkar, Mokshad
; Patel, Nirav
; Vekariya, Nehal
; Smith, J. Gustav
LU
; Kalra, Rajat
; Chahal, C. Anwar A.
; Semsarian, Christopher
and Li, Peng
, et al. (More)
- Shetty, Naman S.
; Pampana, Akhil
; Gaonkar, Mokshad
; Patel, Nirav
; Vekariya, Nehal
; Smith, J. Gustav
LU
; Kalra, Rajat
; Chahal, C. Anwar A.
; Semsarian, Christopher
; Li, Peng
; Arora, Garima
and Arora, Pankaj
(Less)
- organization
- publishing date
- 2025-06
- 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}},
}