Sex-specific genetic determinants of right ventricular structure and function
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Author(s)
Type
Journal Article
Abstract
Rationale: Although sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown.
Objectives: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation.
Methods: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK National Institute for Health Research BioResource Rare Diseases study.
Measurements and Main Results: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function, and sex hormone concentrations. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A (bone morphogenetic protein receptor type 1A) and a locus for RV end-systolic volume near DMRT2 (doublesex and mab-3 related transcription factor 2). Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size, 0.16 L/min/m2), despite similar RV afterload.
Conclusions: BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.
Objectives: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation.
Methods: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK National Institute for Health Research BioResource Rare Diseases study.
Measurements and Main Results: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function, and sex hormone concentrations. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A (bone morphogenetic protein receptor type 1A) and a locus for RV end-systolic volume near DMRT2 (doublesex and mab-3 related transcription factor 2). Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size, 0.16 L/min/m2), despite similar RV afterload.
Conclusions: BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.
Date Issued
2025-01-01
Date Acceptance
2024-10-07
Citation
American Journal of Respiratory and Critical Care Medicine, 2025, 211 (1), pp.113-123
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
113
End Page
123
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
211
Issue
1
Copyright Statement
Copyright © 2024 American Thoracic Society This is the author’s accepted manuscript made available under a CC-BY licence in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy)
License URL
Sponsor
British Heart Foundation
British Heart Foundation
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39374572
Grant Number
RG/F/22/110078
FS/SBSRF/22/31025
Subjects
Gender
Genetics
Pulmonary arterial hypertension
Right ventricle
Sex
11 Medical and Health Sciences
Respiratory System
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-01-01