Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function

Abstract

Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively.In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10(-6)) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure.

Figure 1

Study sample. MESA: Multi-ethnic Study of Atherosclerosis; MRI: magnetic resonance imaging; RV: right ventricle.

Figure 2

Linkage disequilibrium plot for CYP1B1 in African–American women. The white bar represents a chromosome with black lines indicating sequenced single nucleotide polymorphisms (SNPs) in a gene. The colour of a diamond for the intersection of two SNPs indicates likelihood of non-random genetic reassortment such that red regions are most highly correlated (summarised numerically as D′ value). ^#: SNPs of interest. SNP rs162561 was associated with higher right ventricular ejection fraction (RVEF) in African-American women in this study. SNP rs1800440 has been associated with pulmonary arterial hypertension penetrance in women with bone morphogenetic protein receptor type 2 mutations, which is in tight linkage disequilibrium with SNP rs162561 (D′=0.76) [4]. SNP rs1056836 has been associated with breast and lung cancer risk in some studies, also in tight LD with SNP rs162561 (D′=0.96) [–31]. Block 2 was associated with RVEF in African-Americans (global p<7.2×10⁻⁶), whites (global p=0.05), and possibly Hispanics (global p=0.13).

Figure 3

Natural log-transformed testosterone parameter estimates with 95% confidence intervals for right ventricular ejection fraction stratified by androgen receptor genotype for rs1337080 in white men. Models were adjusted for age, height, weight, study site, top three principal components (bottom panel) and left ventricular ejection fraction (top panel). RVEF=right ventricular ejection fraction; LVEF=left ventricular ejection fraction.