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

Anna L. Eriksson, John R.B. 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 Nielson, Inga ProkopenkoStephen 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 Orwoll, Pamela Ouyang, Liesbeth Vandenput, Frederick C.W. Wu, Frank H. de Jong, Shalender Bhasin, Douglas P. Kiel, Claes Ohlsson

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)991-1004
Number of pages14
JournalThe Journal of clinical endocrinology and metabolism
Volume103
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Bone Density
Estradiol
Bone
Estrogens
Steroid 11-beta-Hydroxylase
Minerals
X Chromosome
Chromosomes
Serum
Mendelian Randomization Analysis
Men's Health
Estrone
Genome-Wide Association Study
Insulin Resistance
Spine
Genes
Alleles
Outcome Assessment (Health Care)
Health
Insulin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Eriksson, A. L., Perry, J. R. B., Coviello, A. D., Delgado, G. E., Ferrucci, L., Hoffman, A. R., ... Ohlsson, C. (2018). Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men. The Journal of clinical endocrinology and metabolism, 103(3), 991-1004. https://doi.org/10.1210/jc.2017-02060

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men. / Eriksson, Anna L.; Perry, John R.B.; Coviello, Andrea D.; Delgado, Graciela E.; Ferrucci, Luigi; Hoffman, Andrew R.; Huhtaniemi, Ilpo T.; Ikram, M. Arfan; Karlsson, Magnus K.; Kleber, Marcus E.; Laughlin, Gail A.; Liu, Yongmei; Lorentzon, Mattias; Lunetta, Kathryn L.; Mellström, Dan; Murabito, Joanne M.; Murray, Anna; Nethander, Maria; Nielson, Carrie; Prokopenko, Inga; Pye, Stephen R.; Raffel, Leslie J.; Rivadeneira, Fernando; Srikanth, Priya; Stolk, Lisette; Teumer, Alexander; Travison, Thomas G.; Uitterlinden, André G.; Vaidya, Dhananjay; Vanderschueren, Dirk; Zmuda, Joseph M.; März, Winfried; Orwoll, Eric; Ouyang, Pamela; Vandenput, Liesbeth; Wu, Frederick C.W.; de Jong, Frank H.; Bhasin, Shalender; Kiel, Douglas P.; Ohlsson, Claes.

In: The Journal of clinical endocrinology and metabolism, Vol. 103, No. 3, 01.03.2018, p. 991-1004.

Research output: Contribution to journalArticle

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, C, 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, E, Ouyang, P, Vandenput, L, Wu, FCW, de Jong, FH, Bhasin, S, Kiel, DP & Ohlsson, C 2018, 'Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men', The Journal of clinical endocrinology and metabolism, vol. 103, no. 3, pp. 991-1004. https://doi.org/10.1210/jc.2017-02060
Eriksson, Anna L. ; Perry, John R.B. ; Coviello, Andrea D. ; Delgado, Graciela E. ; Ferrucci, Luigi ; Hoffman, Andrew R. ; Huhtaniemi, Ilpo T. ; Ikram, M. Arfan ; Karlsson, Magnus K. ; Kleber, Marcus E. ; Laughlin, Gail A. ; Liu, Yongmei ; Lorentzon, Mattias ; Lunetta, Kathryn L. ; Mellström, Dan ; Murabito, Joanne M. ; Murray, Anna ; Nethander, Maria ; Nielson, Carrie ; Prokopenko, Inga ; Pye, Stephen R. ; Raffel, Leslie J. ; Rivadeneira, Fernando ; Srikanth, Priya ; Stolk, Lisette ; Teumer, Alexander ; Travison, Thomas G. ; Uitterlinden, André G. ; Vaidya, Dhananjay ; Vanderschueren, Dirk ; Zmuda, Joseph M. ; März, Winfried ; Orwoll, Eric ; Ouyang, Pamela ; Vandenput, Liesbeth ; Wu, Frederick C.W. ; de Jong, Frank H. ; Bhasin, Shalender ; Kiel, Douglas P. ; Ohlsson, Claes. / Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men. In: The Journal of clinical endocrinology and metabolism. 2018 ; Vol. 103, No. 3. pp. 991-1004.
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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.",
author = "Eriksson, {Anna L.} and Perry, {John R.B.} and Coviello, {Andrea D.} and Delgado, {Graciela E.} and Luigi Ferrucci and Hoffman, {Andrew R.} and Huhtaniemi, {Ilpo T.} and Ikram, {M. Arfan} and Karlsson, {Magnus K.} and Kleber, {Marcus E.} and Laughlin, {Gail A.} and Yongmei Liu and Mattias Lorentzon and Lunetta, {Kathryn L.} and Dan Mellstr{\"o}m and Murabito, {Joanne M.} and Anna Murray and Maria Nethander and Carrie Nielson and Inga Prokopenko and Pye, {Stephen R.} and Raffel, {Leslie J.} and Fernando Rivadeneira and Priya Srikanth and Lisette Stolk and Alexander Teumer and Travison, {Thomas G.} and Uitterlinden, {Andr{\'e} G.} and Dhananjay Vaidya and Dirk Vanderschueren and Zmuda, {Joseph M.} and Winfried M{\"a}rz and Eric Orwoll and Pamela Ouyang and Liesbeth Vandenput and Wu, {Frederick C.W.} and {de Jong}, {Frank H.} and Shalender Bhasin and Kiel, {Douglas P.} and Claes Ohlsson",
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T1 - Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men

AU - Eriksson, Anna L.

AU - Perry, John R.B.

AU - Coviello, Andrea D.

AU - Delgado, Graciela E.

AU - Ferrucci, Luigi

AU - Hoffman, Andrew R.

AU - Huhtaniemi, Ilpo T.

AU - Ikram, M. Arfan

AU - Karlsson, Magnus K.

AU - Kleber, Marcus E.

AU - Laughlin, Gail A.

AU - Liu, Yongmei

AU - Lorentzon, Mattias

AU - Lunetta, Kathryn L.

AU - Mellström, Dan

AU - Murabito, Joanne M.

AU - Murray, Anna

AU - Nethander, Maria

AU - Nielson, Carrie

AU - Prokopenko, Inga

AU - Pye, Stephen R.

AU - Raffel, Leslie J.

AU - Rivadeneira, Fernando

AU - Srikanth, Priya

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Travison, Thomas G.

AU - Uitterlinden, André G.

AU - Vaidya, Dhananjay

AU - Vanderschueren, Dirk

AU - Zmuda, Joseph M.

AU - März, Winfried

AU - Orwoll, Eric

AU - Ouyang, Pamela

AU - Vandenput, Liesbeth

AU - Wu, Frederick C.W.

AU - de Jong, Frank H.

AU - Bhasin, Shalender

AU - Kiel, Douglas P.

AU - Ohlsson, Claes

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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