TY - JOUR
T1 - Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function
AU - Ventetuolo, Corey E.
AU - Mitra, Nandita
AU - Wan, Fei
AU - Manichaikul, Ani
AU - Barr, R. Graham
AU - Johnson, Craig
AU - Bluemke, David A.
AU - Lima, Joao A.C.
AU - Tandri, Hari
AU - Ouyang, Pamela
AU - Kawut, Steven M.
N1 - Funding Information:
Support statement: This work was completed with support from the American Heart Association 11FTF7400032, National Institutes of Health P20GM103652 and K24 HL103844. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts R01-HL086719, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR-000040. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Funding information for this article has been deposited with FundRef. This manuscript has been reviewed by the MESA Investigators for scientific content and consistency of data interpretation with previous MESA publications. Significant comments have been incorporated prior to submission for publication. The authors thank the other investigators, staff, and participants of MESA for their valuable contributions. A full list of participating MESA Investigators and institutions can be found at www.mesa-nhlbi.org.
Publisher Copyright:
Copyright © 2016 by the European Respiratory Society.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958078249&partnerID=8YFLogxK
U2 - 10.1183/13993003.01083-2015
DO - 10.1183/13993003.01083-2015
M3 - Article
C2 - 26647441
AN - SCOPUS:84958078249
SN - 0903-1936
VL - 47
SP - 553
EP - 563
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
ER -