| Title: | Sex-specific Genetic Determinants of Right Ventricular Structure and Function. |
| Journal: | American Journal of Respiratory and Critical Care Medicine |
| Published: | 7 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39374572/ |
| DOI: | https://doi.org/10.1164/rccm.202404-0721oc |
| URL: | https://doi.org/10.1101/2024.02.06.23300256 |
Publication 13330
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Abstract
RATIONALE: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown.</p>
OBJECTIVES: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation.</p>
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 NIHR BioResource Rare Diseases study.</p>
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 levels. 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 and a locus for RV end-systolic volume near DMRT2. 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.</p>
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.</p>
13 Authors
- Lars Harbaum
- Jan K Hennigs
- Julian Pott
- Jonna Ostermann
- Christoph R Sinning
- Arunashis Sau
- Ewa Sieliwonczyk
- Fu Siong Ng
- Christopher J Rhodes
- Khodr Tello
- Hans Klose
- Stefan Gräf
- Martin R Wilkins
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