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

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 5 , 12 , 13 , 1 , 14 , 15 , 16 , 1 , 14 , 17 , 3 , 1 , 18 , 19 , 20 , 21 , 22 , 10 , 23 , 18 , 23 , 24 , 25 , 26 , 10 , 23 , 27 , 28 , 29 , 30 , 31 , 32 , 27 , 1 , 33 , 23 , 34 , 16 , 26 , 1
      The Journal of Clinical Endocrinology and Metabolism
      Endocrine Society

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          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.

          Abstract

          CYP19A1 was the main regulator of estrogen levels in this GWAS, with additional loci on chromosome X and in TRIM4 and CYP11B1/B2. Findings in the study strengthen the importance of E2 for bone health.

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          Most cited references35

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          Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones.

          Significant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in 1988. Major developments include the cloning, identification, and characterization of multiple isoforms of 3beta-hydroxysteroid dehydrogenase, which play a critical role in the biosynthesis of all steroid hormones and 17beta-hydroxysteroid dehydrogenase where specific isoforms are essential for the final step in active steroid hormone biosynthesis. Advances have taken place in our understanding of the unique manner that determines tissue-specific expression of P450aromatase through the utilization of alternative promoters. In recent years, evidence has been obtained for the expression of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner. This review presents a detailed description of the enzymes involved in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta.
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            Predictive value of BMD for hip and other fractures.

            The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.
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              TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination.

              RIG-I is a pivotal cytoplasmic sensor that recognizes different species of viral RNAs. This recognition leads to activation of the transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. In this study, we identified the TRIM family protein TRIM4 as a positive regulator of RIG-I-mediated IFN induction. Overexpression of TRIM4 potentiated virus-triggered activation of IRF3 and NF-κB, as well as IFN-β induction, whereas knockdown of TRIM4 had opposite effects. Mechanistically, TRIM4 associates with RIG-I and targets it for K63-linked polyubiquitination. Our findings demonstrate that TRIM4 is an important regulator of the virus-induced IFN induction pathways by mediating RIG-I for K63-linked ubiquitination.
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                Author and article information

                Journal
                J Clin Endocrinol Metab
                J. Clin. Endocrinol. Metab
                jcem
                The Journal of Clinical Endocrinology and Metabolism
                Endocrine Society (Washington, DC )
                0021-972X
                1945-7197
                March 2018
                09 January 2018
                09 January 2018
                : 103
                : 3
                : 991-1004
                Affiliations
                [1 ]Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
                [2 ]Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
                [3 ]University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
                [4 ]Duke University School of Medicine, Durham, North Carolina
                [5 ]Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, 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
                [9 ]Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
                [10 ]Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
                [11 ]Department of Orthopaedics and Clinical Sciences, Skåne University Hospital, Lund University, Malmö, 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
                [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
                [20 ]Hammersmith Hospital, London, 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
                [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
                [24 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [25 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
                [26 ]Institute for Aging Research, Hebrew Senior Life and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
                [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
                [29 ]Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
                [30 ]Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
                [31 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, 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
                [34 ]Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
                Author notes

                These authors contributed equally to this work

                These authors were joint senior authors on this work.

                Correspondence and Reprint Requests:  Claes Ohlsson, MD, PhD, Centre for Bone and Arthritis Research, Klin Farm Laboratory, Vita Stråket 11, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden. E-mail: claes.ohlsson@ 123456medic.gu.se .
                Article
                jcem_201702060
                10.1210/jc.2017-02060
                5868407
                29325096
                aa24c0b8-8417-40e7-8e56-5c694de9213a

                This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).

                History
                : 17 September 2017
                : 04 January 2018
                Page count
                Pages: 14
                Categories
                Clinical Research Articles
                Reproductive Biology and Sex-Based Medicine

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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