Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men

• Verfasst von: Eriksson, Anna L. [VerfasserIn]
• Verfasst von: Delgado Gonzales de Kleber, Graciela [VerfasserIn]
• Verfasst von: Kleber, Marcus E. [VerfasserIn]
• Titel: Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men
• Verf.angabe: Anna L Eriksson, John RB Perry, Andrea D Coviello, Graciela E Delgado, Luigi Ferrucci, Andrew R Hoffman, Ilpo T Huhtaniemi, M Arfan Ikram, Magnus K Karlsson, Marcus E Kleber, Gail A Laughlin, Yongmei Liu, Mattias Lorentzon, Kathryn L Lunetta, Dan Mellström, Joanne M Murabito, Anna Murray, Maria Nethander, Carrie M Nielson, Inga Prokopenko, Stephen R Pye, Leslie J Raffel, Fernando Rivadeneira, Priya Srikanth, Lisette Stolk, Alexander Teumer, Thomas G Travison, André G Uitterlinden, Dhananjay Vaidya, Dirk Vanderschueren, Joseph M Zmuda, Winfried März, Eric S Orwoll, Pamela Ouyang, Liesbeth Vandenput, Frederick CW Wu, Frank H de Jong, Shalender Bhasin, Douglas P Kiel, and Claes Ohlsson
• E-Jahr: 2018
• Jahr: 9 January 2018
• Umfang: 14 S.
• Fussnoten: Gesehen am 04.07.2019
• Titel Quelle: Enthalten in: The journal of clinical endocrinology & metabolism
• Ort Quelle: Oxford : Oxford University Press, 1941
• Jahr Quelle: 2018
• Band/Heft Quelle: 103(2018), 3, Seite 991-1004
• ISSN Quelle: 1945-7197
• DOI: doi:10.1210/jc.2017-02060
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1668597667

Abstract

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 3 1028) and Xq27.3, rs5951794 (P = 3.1 3 10210). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 3 10223), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 3 10214), and CYP11B1/B2 (rs10093796, P = 1.2 3 1028). 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 3 10212). 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. (J Clin Endocrinol Metab 103: 991-1004, 2018)