Sex-specific Genetic Determinants of Right Ventricular Structure and Function

Overview

Journal Am J Respir Crit Care Med

Specialty Critical Care

Date 2024 Oct 7

PMID 39374572

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 Graf

Martin R Wilkins

Affiliations

Soon will be listed here.

Abstract

Rationale: While 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 NIHR 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 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 and a locus for RV end-systolic volume near . Epigenetic data in RV tissue indicate that variation at the locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of was significantly associated with cardiac index (effect size 0.16 l/min/m), despite similar RV afterload.

Conclusions: 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.

Citing Articles

Decoding Sex Differences in Right Ventricular Function through .

Toth E, van Wezenbeek J, de Man F Am J Respir Crit Care Med. 2024; .

PMID: 39556411 PMC: 11755359. DOI: 10.1164/rccm.202410-2048ED.

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