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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 L1
  • Perry, John R B2, 3
  • Coviello, Andrea D4
  • Delgado, Graciela E5
  • Ferrucci, Luigi6
  • Hoffman, Andrew R7
  • Huhtaniemi, Ilpo T8, 9
  • Ikram, M Arfan10
  • Karlsson, Magnus K11
  • Kleber, Marcus E5
  • Laughlin, Gail A12
  • Liu, Yongmei13
  • Lorentzon, Mattias1, 14
  • Lunetta, Kathryn L15, 16
  • Mellström, Dan1, 14
  • Murabito, Joanne M17
  • Murray, Anna3
  • Nethander, Maria1
  • Nielson, Carrie M18
  • Prokopenko, Inga19, 20
  • And 20 more
  • 1 Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. , (Sweden)
  • 2 Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom. , (United Kingdom)
  • 3 University of Exeter Medical School, University of Exeter, Exeter, United Kingdom. , (United Kingdom)
  • 4 Duke University School of Medicine, Durham, North Carolina.
  • 5 Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. , (Germany)
  • 6 Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland.
  • 7 Division of Endocrinology, Stanford University School of Medicine, Stanford, California.
  • 8 Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, United Kingdom. , (United Kingdom)
  • 9 Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland. , (Finland)
  • 10 Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. , (Netherlands)
  • 11 Department of Orthopaedics and Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden. , (Sweden)
  • 12 Family Medicine and Public Health, University of California-San Diego, San Diego, California.
  • 13 Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
  • 14 Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg and Geriatric Medicine, Sahlgrenska University Hospital, Mölndal, Sweden. , (Sweden)
  • 15 Boston University School of Public Health, Boston, Massachusetts.
  • 16 Framingham Heart Study, Framingham, Massachusetts.
  • 17 Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 18 School of Public Health, Oregon Health & Science University, Portland, Oregon.
  • 19 Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom. , (United Kingdom)
  • 20 Hammersmith Hospital, London, United Kingdom. , (United Kingdom)
  • 21 Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom. , (United Kingdom)
  • 22 Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, California.
  • 23 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. , (Netherlands)
  • 24 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. , (Germany)
  • 25 Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. , (Germany)
  • 26 Institute for Aging Research, Hebrew Senior Life and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. , (Israel)
  • 27 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 28 Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium. , (Belgium)
  • 29 Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 30 Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany. , (Germany)
  • 31 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. , (Austria)
  • 32 Bone & Mineral Unit, Oregon Health & Science University, Portland, Oregon.
  • 33 Andrology Research Unit, Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester, United Kingdom. , (United Kingdom)
  • 34 Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Published Article
The Journal of Clinical Endocrinology & Metabolism
The Endocrine Society
Publication Date
Mar 01, 2018
DOI: 10.1210/jc.2017-02060
PMID: 29325096


Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. To investigate the genetic regulation of serum E2 and E1 in men. Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Genetic determinants of serum E2 and E1 levels. 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. 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.

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