Skip to main content
Erschienen in: Calcified Tissue International 3/2021

17.10.2020 | Original Research

Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study

verfasst von: Zihao Qu, Jiuzhou Jiang, Fangkun Yang, Jiawei Huang, Jianqiang Zhao, Shigui Yan

Erschienen in: Calcified Tissue International | Ausgabe 3/2021

Einloggen, um Zugang zu erhalten

Abstract

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses. From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15–30, 30–45, 45–60, 60 or more years old) (n = 67,358). Inverse causal associations was observed between SHBG levels and FA BMD (Effect = − 0.26; 95% CI − 0.49 to − 0.04; P = 0.022), HL eBMD (Effect = − 0.09; 95% CI − 0.12 to − 0.06; P = 3.19 × 10–9), and total-body BMD in people aged 45–60 years (Effect = − 0.16; 95% CI − 0.31 to − 2.4 × 10–3; P = 0.047) and over 60 years (Effect = − 0.19; 95% CI − 0.33 to − 0.05; P = 0.006). Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45 years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Klibanski A, Adams-Campbell L, Bassford TL, Blair SN, Boden SD, Dickersin K et al (2001) Osteoporosis prevention, diagnosis, and therapy. J Am Med Assoc 285(6):785–795 Klibanski A, Adams-Campbell L, Bassford TL, Blair SN, Boden SD, Dickersin K et al (2001) Osteoporosis prevention, diagnosis, and therapy. J Am Med Assoc 285(6):785–795
2.
Zurück zum Zitat Holroyd C, Cooper C, Dennison E (2008) Epidemiology of osteoporosis. Best Pract Res Clin Endocrinol Metab 22(5):671–685PubMed Holroyd C, Cooper C, Dennison E (2008) Epidemiology of osteoporosis. Best Pract Res Clin Endocrinol Metab 22(5):671–685PubMed
3.
Zurück zum Zitat Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S et al (2010) 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 182(17):1864–1873PubMedPubMedCentral Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S et al (2010) 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 182(17):1864–1873PubMedPubMedCentral
4.
Zurück zum Zitat Compston J, Bowring C, Cooper A, Cooper C, Davies C, Francis R et al (2013) Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas 75(4):392–396PubMed Compston J, Bowring C, Cooper A, Cooper C, Davies C, Francis R et al (2013) Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas 75(4):392–396PubMed
5.
Zurück zum Zitat Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23(3):303–326PubMed Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23(3):303–326PubMed
6.
Zurück zum Zitat Burrows M, Nevill AM, Bird S, Simpson D (2003) Physiological factors associated with low bone mineral density in female endurance runners. Br J Sports Med 37(1):67–71PubMedPubMedCentral Burrows M, Nevill AM, Bird S, Simpson D (2003) Physiological factors associated with low bone mineral density in female endurance runners. Br J Sports Med 37(1):67–71PubMedPubMedCentral
7.
Zurück zum Zitat Asomaning K, Bertone-Johnson ER, Nasca PC, Hooven F, Pekow PS (2006) The association between body mass index and osteoporosis in patients referred for a bone mineral density examination. J Women’s Health 15(9):1028–1034 Asomaning K, Bertone-Johnson ER, Nasca PC, Hooven F, Pekow PS (2006) The association between body mass index and osteoporosis in patients referred for a bone mineral density examination. J Women’s Health 15(9):1028–1034
8.
Zurück zum Zitat Hernandez C, Beaupre G, Carter D (2003) A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 14(10):843–847PubMed Hernandez C, Beaupre G, Carter D (2003) A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 14(10):843–847PubMed
9.
10.
Zurück zum Zitat Silvennoinen J, Lehtola J, Niemelä S (1996) Smoking is a risk factor for osteoporosis in women with inflammatory bowel disease. Scand J Gastroenterol 31(4):367–371PubMed Silvennoinen J, Lehtola J, Niemelä S (1996) Smoking is a risk factor for osteoporosis in women with inflammatory bowel disease. Scand J Gastroenterol 31(4):367–371PubMed
11.
Zurück zum Zitat Legrand E, Hedde C, Gallois Y, Degasne I, De Casson FB, Mathieu E et al (2001) Osteoporosis in men: a potential role for the sex hormone binding globulin. Bone 29(1):90–95PubMed Legrand E, Hedde C, Gallois Y, Degasne I, De Casson FB, Mathieu E et al (2001) Osteoporosis in men: a potential role for the sex hormone binding globulin. Bone 29(1):90–95PubMed
12.
Zurück zum Zitat Petra PH (1991) The plasma sex steroid binding protein (SBP or SHBG): A critical review of recent developments on the structure, molecular biology and function. J Steroid Biochem Mol Biol 40(4–6):735–753PubMed Petra PH (1991) The plasma sex steroid binding protein (SBP or SHBG): A critical review of recent developments on the structure, molecular biology and function. J Steroid Biochem Mol Biol 40(4–6):735–753PubMed
13.
Zurück zum Zitat De Ronde W, Van Der Schouw YT, Muller M, Grobbee DE, Gooren LJ, Pols HA et al (2005) Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men. J Clin Endocrinol Metab 90(1):157–162PubMed De Ronde W, Van Der Schouw YT, Muller M, Grobbee DE, Gooren LJ, Pols HA et al (2005) Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men. J Clin Endocrinol Metab 90(1):157–162PubMed
14.
Zurück zum Zitat Maggio M, Lauretani F, Aloe R, Lind L, Cederholm T, Ceda G (2017) The role of SHBG in executive function in older persons: the PIVUS study. Innovat Aging 1(1):1150 Maggio M, Lauretani F, Aloe R, Lind L, Cederholm T, Ceda G (2017) The role of SHBG in executive function in older persons: the PIVUS study. Innovat Aging 1(1):1150
15.
Zurück zum Zitat Zha X-Y, Hu Y, Pang X-N, Zhu J-H, Chang G-L, Li L (2014) Sex hormone-binding globulin (SHBG) as an independent determinant of bone mineral density (BMD) among Chinese middle-aged and elderly men. Endocrine 47(2):590–597PubMed Zha X-Y, Hu Y, Pang X-N, Zhu J-H, Chang G-L, Li L (2014) Sex hormone-binding globulin (SHBG) as an independent determinant of bone mineral density (BMD) among Chinese middle-aged and elderly men. Endocrine 47(2):590–597PubMed
16.
Zurück zum Zitat Napoli N, Varadharajan A, Rini GB, Del Fiacco R, Yarramaneni J, Mumm S et al (2009) Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density. Bone 45(6):1169–1174PubMedPubMedCentral Napoli N, Varadharajan A, Rini GB, Del Fiacco R, Yarramaneni J, Mumm S et al (2009) Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density. Bone 45(6):1169–1174PubMedPubMedCentral
17.
Zurück zum Zitat Hsu B, Seibel MJ, Cumming RG, Blyth FM, Naganathan V, Bleicher K et al (2016) Progressive temporal change in serum SHBG, but not in serum testosterone or estradiol, is associated with bone loss and incident fractures in older men: the Concord Health and Ageing in Men Project. J Bone Miner Res 31(12):2115–2122PubMed Hsu B, Seibel MJ, Cumming RG, Blyth FM, Naganathan V, Bleicher K et al (2016) Progressive temporal change in serum SHBG, but not in serum testosterone or estradiol, is associated with bone loss and incident fractures in older men: the Concord Health and Ageing in Men Project. J Bone Miner Res 31(12):2115–2122PubMed
18.
Zurück zum Zitat Jee W (2000) Principles in bone physiology. J Musculoskelet Neuronal Interact 1(1):11–13PubMed Jee W (2000) Principles in bone physiology. J Musculoskelet Neuronal Interact 1(1):11–13PubMed
19.
Zurück zum Zitat Evans DM, Davey SG (2015) Mendelian randomization: new applications in the coming age of hypothesis-free causality. Annu Rev Genomics Hum Genet 16:327–350PubMed Evans DM, Davey SG (2015) Mendelian randomization: new applications in the coming age of hypothesis-free causality. Annu Rev Genomics Hum Genet 16:327–350PubMed
20.
Zurück zum Zitat Davey Smith G, Hemani G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23(R1):R89–R98PubMedPubMedCentral Davey Smith G, Hemani G (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23(R1):R89–R98PubMedPubMedCentral
21.
Zurück zum Zitat Larsson SC, Michaëlsson K, Burgess S (2019) Mendelian randomization in the bone field. Bone 126:51–58PubMed Larsson SC, Michaëlsson K, Burgess S (2019) Mendelian randomization in the bone field. Bone 126:51–58PubMed
22.
Zurück zum Zitat Ebrahim S, Smith GD (2008) Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum Genet 123(1):15–33PubMed Ebrahim S, Smith GD (2008) Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum Genet 123(1):15–33PubMed
23.
Zurück zum Zitat Guo R, Wu L, Fu Q (2018) Is There causal relationship of smoking and alcohol consumption with bone mineral density? A mendelian randomization study. Calcif Tissue Int 103(5):546–553PubMed Guo R, Wu L, Fu Q (2018) Is There causal relationship of smoking and alcohol consumption with bone mineral density? A mendelian randomization study. Calcif Tissue Int 103(5):546–553PubMed
24.
Zurück zum Zitat Kemp JP, Sayers A, Smith GD, Tobias JH, Evans DM (2016) Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children. Int J Epidemiol 45(5):1560–1572PubMedPubMedCentral Kemp JP, Sayers A, Smith GD, Tobias JH, Evans DM (2016) Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children. Int J Epidemiol 45(5):1560–1572PubMedPubMedCentral
25.
Zurück zum Zitat Ahmad OS, Leong A, Miller JA, Morris JA, Forgetta V, Mujammami M et al (2017) A mendelian randomization study of the effect of type-2 diabetes and glycemic traits on bone mineral density. J Bone Miner Res 32(5):1072–1081PubMed Ahmad OS, Leong A, Miller JA, Morris JA, Forgetta V, Mujammami M et al (2017) A mendelian randomization study of the effect of type-2 diabetes and glycemic traits on bone mineral density. J Bone Miner Res 32(5):1072–1081PubMed
26.
Zurück zum Zitat Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimäki T, Keildson S et al (2012) A genome-wide association meta-analysis of circulating sex hormone–binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet 8(7):e1002805PubMedPubMedCentral Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimäki T, Keildson S et al (2012) A genome-wide association meta-analysis of circulating sex hormone–binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet 8(7):e1002805PubMedPubMedCentral
27.
Zurück zum Zitat Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS et al (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18(11):1947–1954PubMed Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS et al (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18(11):1947–1954PubMed
28.
Zurück zum Zitat Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE et al (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 49(10):1468PubMedPubMedCentral Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE et al (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 49(10):1468PubMedPubMedCentral
29.
Zurück zum Zitat Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ et al (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526(7571):112PubMedPubMedCentral Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ et al (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526(7571):112PubMedPubMedCentral
30.
Zurück zum Zitat Kim SK (2018) Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS ONE 13(7):e0200785PubMedPubMedCentral Kim SK (2018) Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS ONE 13(7):e0200785PubMedPubMedCentral
31.
Zurück zum Zitat Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS et al (2018) Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet 102(1):88–102PubMedPubMedCentral Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS et al (2018) Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet 102(1):88–102PubMedPubMedCentral
32.
Zurück zum Zitat Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez M, Muñoz-Torres M (2013) SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporos Int 24(2):713–719PubMed Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez M, Muñoz-Torres M (2013) SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporos Int 24(2):713–719PubMed
33.
Zurück zum Zitat Rapuri PB, Gallagher JC, Haynatzki G (2004) Endogenous levels of serum estradiol and sex hormone binding globulin determine bone mineral density, bone remodeling, the rate of bone loss, and response to treatment with estrogen in elderly women. J Clin Endocrinol Metab 89(10):4954–4962PubMed Rapuri PB, Gallagher JC, Haynatzki G (2004) Endogenous levels of serum estradiol and sex hormone binding globulin determine bone mineral density, bone remodeling, the rate of bone loss, and response to treatment with estrogen in elderly women. J Clin Endocrinol Metab 89(10):4954–4962PubMed
34.
Zurück zum Zitat Woods GN, Huang M-H, Cawthon PM, Laughlin GA, Schousboe JT, McDaniels-Davidson C et al (2016) SHBG, sex steroids, and kyphosis in older men: the MrOS study. J Bone Miner Res 31(12):2123–2128PubMedPubMedCentral Woods GN, Huang M-H, Cawthon PM, Laughlin GA, Schousboe JT, McDaniels-Davidson C et al (2016) SHBG, sex steroids, and kyphosis in older men: the MrOS study. J Bone Miner Res 31(12):2123–2128PubMedPubMedCentral
35.
Zurück zum Zitat Wei S, Jones G, Thomson R, Otahal P, Dwyer T, Venn A (2010) Menstrual irregularity and bone mass in premenopausal women: cross-sectional associations with testosterone and SHBG. BMC Musculoskelet Disord 11:288PubMedPubMedCentral Wei S, Jones G, Thomson R, Otahal P, Dwyer T, Venn A (2010) Menstrual irregularity and bone mass in premenopausal women: cross-sectional associations with testosterone and SHBG. BMC Musculoskelet Disord 11:288PubMedPubMedCentral
36.
Zurück zum Zitat Bilha SC, Branisteanu D, Buzduga C, Constantinescu D, Cianga P, Anisie E et al (2018) Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men. J Endocrinol Invest. 41(8):995–1003PubMed Bilha SC, Branisteanu D, Buzduga C, Constantinescu D, Cianga P, Anisie E et al (2018) Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men. J Endocrinol Invest. 41(8):995–1003PubMed
37.
Zurück zum Zitat Arathimos R, Millard LAC, Bell JA, Relton CL, Suderman M (2020) Impact of sex hormone-binding globulin on the human phenome. Hum Mol Genet 29(11):1824–1832PubMedPubMedCentral Arathimos R, Millard LAC, Bell JA, Relton CL, Suderman M (2020) Impact of sex hormone-binding globulin on the human phenome. Hum Mol Genet 29(11):1824–1832PubMedPubMedCentral
38.
Zurück zum Zitat Havill LM, Mahaney MC, Binkley L, Specker TL (2007) Effects of genes, sex, age, and activity on BMC, bone size, and areal and volumetric BMD. J Bone Mineral Res 22(5):737–746 Havill LM, Mahaney MC, Binkley L, Specker TL (2007) Effects of genes, sex, age, and activity on BMC, bone size, and areal and volumetric BMD. J Bone Mineral Res 22(5):737–746
39.
Zurück zum Zitat Handelsman DJ, Sikaris K, Ly LP (2016) Estimating age-specific trends in circulating testosterone and sex hormone-binding globulin in males and females across the lifespan. Ann Clin Biochem 53(3):377–384PubMed Handelsman DJ, Sikaris K, Ly LP (2016) Estimating age-specific trends in circulating testosterone and sex hormone-binding globulin in males and females across the lifespan. Ann Clin Biochem 53(3):377–384PubMed
40.
Zurück zum Zitat Elmlinger MW, Kühnel W, Wormstall H, Döller PC (2005) Reference intervals for testosterone, androstenedione and SHBG levels in healthy females and males from birth until old age. Clin Lab 51(11–12):625–632PubMed Elmlinger MW, Kühnel W, Wormstall H, Döller PC (2005) Reference intervals for testosterone, androstenedione and SHBG levels in healthy females and males from birth until old age. Clin Lab 51(11–12):625–632PubMed
41.
Zurück zum Zitat Jing Y, Wang X, Yu J, Wang X, Zhou Y, Tao B et al (2019) Associations of serum sex hormone binding globulin with bone mineral densities and higher 10-year probability of fractures in postmenopausal women with type 2 diabetes mellitus. Ann Transl Med 7(18):457PubMedPubMedCentral Jing Y, Wang X, Yu J, Wang X, Zhou Y, Tao B et al (2019) Associations of serum sex hormone binding globulin with bone mineral densities and higher 10-year probability of fractures in postmenopausal women with type 2 diabetes mellitus. Ann Transl Med 7(18):457PubMedPubMedCentral
42.
Zurück zum Zitat Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32(1):1–22 Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32(1):1–22
43.
Zurück zum Zitat Smith GD, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33(1):30–42PubMed Smith GD, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33(1):30–42PubMed
44.
Zurück zum Zitat Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA (2006) Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 163(5):397–403PubMed Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA (2006) Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 163(5):397–403PubMed
45.
Zurück zum Zitat Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32(5):377–389PubMedPubMedCentral Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32(5):377–389PubMedPubMedCentral
Metadaten
Titel
Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study
verfasst von
Zihao Qu
Jiuzhou Jiang
Fangkun Yang
Jiawei Huang
Jianqiang Zhao
Shigui Yan
Publikationsdatum
17.10.2020
Verlag
Springer US
Erschienen in
Calcified Tissue International / Ausgabe 3/2021
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-020-00770-8

Weitere Artikel der Ausgabe 3/2021

Calcified Tissue International 3/2021 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.