title: 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.
authors.affiliation: Depts of Medicine and Health Services, Policy and Practice, Alpert Medical School of Brown University, Providence, RI, USA corey_ventetuolo@brown.edu.
authors.forename: Corey E
authors.initials: CE
authors.lastname: Ventetuolo
authors.affiliation: Dept of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.affiliation: Dept of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Wan
authors.affiliation: Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.affiliation: Dept of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.affiliation: Dept of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, National Institute for Biomedical Imaging and Bioengineering, Bethesda, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bluemke
authors.affiliation: Dept of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Joao A C
authors.initials: JA
authors.lastname: Lima
authors.affiliation: Dept of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Tandri
authors.affiliation: Dept of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ouyang
authors.affiliation: Dept of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA Dept of Medicine, University of Pennsylvania, Philadelphia, PA, USA Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kawut
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011944:Receptors, Androgen / Q000235:genetics*; D012737:Sex Factors; D013318:Stroke Volume / Q000235:genetics*; D018497:Ventricular Dysfunction, Right / Q000235:genetics*; D016278:Ventricular Function, Right / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D004958:Estradiol; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1