Dataset Information

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

ABSTRACT: Context:Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective:To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants:Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures:Genetic determinants of serum E2 and E1 levels. Results:Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions:Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

SUBMITTER: Eriksson AL

PROVIDER: S-EPMC5868407 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Eriksson Anna L AL Perry John R B JRB Coviello Andrea D AD Delgado Graciela E GE Ferrucci Luigi L Hoffman Andrew R AR Huhtaniemi Ilpo T IT Ikram M Arfan MA Karlsson Magnus K MK Kleber Marcus E ME Laughlin Gail A GA Liu Yongmei Y Lorentzon Mattias M Lunetta Kathryn L KL Mellström Dan D Murabito Joanne M JM Murray Anna A Nethander Maria M Nielson Carrie M CM Prokopenko Inga I Pye Stephen R SR Raffel Leslie J LJ Rivadeneira Fernando F Srikanth Priya P Stolk Lisette L Teumer Alexander A Travison Thomas G TG Uitterlinden André G AG Vaidya Dhananjay D Vanderschueren Dirk D Zmuda Joseph M JM März Winfried W Orwoll Eric S ES Ouyang Pamela P Vandenput Liesbeth L Wu Frederick C W FCW de Jong Frank H FH Bhasin Shalender S Kiel Douglas P DP Ohlsson Claes C

The Journal of clinical endocrinology and metabolism 20180301 3

<h4>Context</h4>Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.<h4>Objective</h4>To investigate the genetic regulation of serum E2 and E1 in men.<h4>Design, setting, and participants</h4>Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.<h4>Main outcome measures</h4>Genetic determinants of serum E2 and E1 levels.<h4>Results</h4>Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolv ...[more]

PMID: 29325096

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Project description:In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10-49 ) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (β = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (β = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Dataset Information

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Publications

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

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