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

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

J Clin Endocrinol Metab. 2018 Jan 09;:

Authors: Eriksson AL, Perry JRB, Coviello AD, Delgado GE, Ferrucci L, Hoffman AR, Huhtaniemi IT, Ikram MA, Karlsson MK, Kleber ME, Laughlin GA, Liu Y, Lorentzon M, Lunetta KL, Mellström D, Murabito JM, Murray A, Nethander M, Nielson CM, Prokopenko I, Pye SR, Raffel LJ, Rivadeneira F, Srikanth P, Stolk L, Teumer A, Travison TG, Uitterlinden AG, Vaidya D, Vanderschueren D, Zmuda JM, März W, Orwoll ES, Ouyang P, Vandenput L, Wu FCW, de Jong FH, Bhasin S, Kiel DP, Ohlsson C

Abstract
Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. No genome-wide association study (GWAS) of estrogen levels has been performed in men of European origin.
Objective: To investigate the genetic regulation of serum E2 and E1 in men.
Design, setting and participants: GWAS 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; FAM9B, rs5934505 (p-value 3.4 x 10-8) and Xq27.3, rs5951794 (p-value 3.1 x 10-10). E1 signals were found in CYP19A1 (rs2899472, p-value 5.5 x 10-23), in TRIM4 (rs17277546, p = 5.8 x 10-14) and in CYP11B1/B2 (rs10093796, p-value 1.2 x 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. 1 pg/ml genetically increased E2 was associated with a 0.048 SD increase in lumbar spine BMD (p-value 2.8 x 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 2 new independent loci on the X-chromosome for E2, one new locus each in TRIM4 and CYP11B1/B2, for E1.

PMID: 29325096 [PubMed - as supplied by publisher]

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