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The role of estrogen receptor-α gene TA polymorphism and aromatase gene TTTA polymorphism on peak bone mass attainment in males: is there an additive negative effect of certain allele combinations?

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Abstract

Idiopathic osteoporosis in males is influenced predominantly by low peak bone mass as a feature under a strong genetic control. Among a number of candidate genes, α-estrogen receptor (ERα) and CYP19 genes are of particular interest due to important role of estrogen in pathophysiology of osteoporosis. In the present study we examined the association of certain allelic combinations of ERα gene thymine–adenine (TA) polymorphism and aromatase gene TTTA polymorphism on bone mineral density (BMD) in young men. The study sample consisted of 92 unrelated healthy male volunteers, aged 21–35. In each subject, lumbar spine and proximal femur BMD, parameters of bone turnover and 25-OHD level were measured. Two ERα (TA) n alleles, allele 19 and allele 21, were found to be associated with lower BMD. The presence of allele 19 was associated with significantly lower lumbar spine (P = 0.006) and trochanter (P = 0.02) BMD while the subjects positive for allele 21 had significantly lower lumbar spine (P = 0.04), trochanter (P = 0.02) and total hip (P = 0.03) BMD. Men with CYP19 (TTTA)7-3/ERα (TA)19 allele combination had significantly lower lumbar spine BMD (P = 0.02) and those with CYP19 (TTTA)7-3/ERα (TA)21 allele combination had significantly lower BMD for all three measurements, i.e. lumbar spine (P = 0.02), femoral neck (P = 0.02) and total hip (P = 0.008). These particular combinations of high-risk alleles were associated with lower median lumbar spine, femoral neck and total hip BMD than either of the allele alone suggesting that negative effect of two risk alleles on peak bone mass add up.

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References

  1. Ralston SH (2002) Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466

    Article  PubMed  CAS  Google Scholar 

  2. Morrison NA, Cheng J, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287

    Article  PubMed  CAS  Google Scholar 

  3. Cusack S, Molgaard C, Michaelsen KF, Jakobsen J, Lamberg-Allardt CJ, Cashman KD (2006) Vitamin D and estrogen receptor-alpha genotype and indices of bone mass and bone turnover in Danish girls. J Bone Miner Metab 24:329–336

    Article  PubMed  CAS  Google Scholar 

  4. Mann V, Ralston H (2003) Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Bone 32:711–717

    Article  PubMed  CAS  Google Scholar 

  5. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689–3698

    Article  PubMed  CAS  Google Scholar 

  6. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061

    Article  PubMed  CAS  Google Scholar 

  7. Vanderschueren D, Boonen S, Ederveen AGH, De Costner R, Van Herck E, Moermans K, Vandenput L, Verstuyf A, Bouillon R (2000) Skeletal effects of estrogen deficiency induced by an aromatase inhibitor in an aged male rat model. Bone 27:611–617

    Article  PubMed  CAS  Google Scholar 

  8. Gennari L, Merlotti D, Martini G, Gonnelli S, Franci B, Campagna S, Lucani B, Dal Canto N, Valenti R, Gennari C, Nuti R (2003) Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab 88:5327–5333

    Article  PubMed  CAS  Google Scholar 

  9. Kastelan D, Grubic Z, Kraljevic I, Duric K, Kardum I, Dusek T, Stingl K, Giljevic Z, Kerhin-Brkljacic V, Suchanek E, Korsic M (2007) Decreased peak bone mass is associated with a 3-bp deletion/insertion of the CYP19 intron 4 polymorphism: a preliminary data from the GOOS study. J Endocrinol Invest 30:465–469

    PubMed  CAS  Google Scholar 

  10. Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, Manolagas SC (2003) Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 111:1651–1664

    PubMed  CAS  Google Scholar 

  11. McCarthy TL, Chang WZ, Liu Y, Centrella M (2003) Runx2 integrates estrogen activity in osteoblasts. J Biol Chem 278:43121–43129

    Article  PubMed  CAS  Google Scholar 

  12. Smith MR, Fallon MA, Lee H, Finkelstein JS (2004) Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 89:3841–3846

    Article  PubMed  CAS  Google Scholar 

  13. Kastelan D, Giljevic Z, Kraljevic I, Korsic M (2006) Selective estrogen receptor modulators: a possible new treatment of osteoporosis in males. Med Hypotheses 67:1052–1053

    Article  PubMed  CAS  Google Scholar 

  14. del Senno L, Aguiari GL, Piva R (1992) Dinucleotide repeat polymorphism in the human estrogen receptor gene. Hum Mol Genet 1:354

    Article  PubMed  CAS  Google Scholar 

  15. Becherini L, Gennari L, Masi L, Mansani R, Massart F, Morelli A, Falchetti A, Gonnelli S, Fiorelli G, Tanini A, Brandi ML (2000) Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor α gene and their relationship to bone mass variation in postmenopausal Italian women. Hum Mol Genet 9:2043–2050

    Article  PubMed  CAS  Google Scholar 

  16. Chen HY, Chen WC, Tsai HD, Hsu CD, Tsai FJm Tsai CH (2001) Relation of the estrogen receptor α gene microsatellite polymorphism to bone mineral density and the susceptibility to osteoporosis in postmenopausal Chinese women in Taiwan. Maturitas 40:143–150

    Article  PubMed  CAS  Google Scholar 

  17. Langdahl BL, Lokke E, Carstens M, Stenkjaer LL, Eriksen EF (2000) A TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not. J Bone Miner Res 15:2222–2230

    Article  PubMed  CAS  Google Scholar 

  18. Albagha AM, McGuigan FE, Reid DM, Ralston SH (2001) Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 16:128–134

    Article  PubMed  CAS  Google Scholar 

  19. Sano M, Inoue S, Hosoi T, Ouchi Y, Emi M, Shiraki M, Orimo H (1995) Association of estrogen receptor nucleotide repeat polymorphism with osteoporosis. Biochem Biophys Res Commun 217:378–383

    Article  PubMed  CAS  Google Scholar 

  20. Yim CH, Choi JT, Choi HA, Kang YS, Moon IG, Yoon HK, Han IK, Kang DH, Han KO (2005) Association of estrogen receptor α gene microsatellite polymorphism with anual changes in bone mineral density in Korean women with hormone replacement therapy. J Bone Miner Metab 23:395–400

    Article  PubMed  CAS  Google Scholar 

  21. Korach KS (1994) Insights from the study of animals lacking functional estrogen receptor. Science 266:1524–1527

    Article  PubMed  CAS  Google Scholar 

  22. Nam HS, Shin MH, Kweon SS, Park KS, Sohn SJ, Rhee JA, Choi JS, Son MH (2005) Association of estrogen receptor-alpha gene polymorphisms with bone mineral density in postmenopausal Korean women. J Bone Miner Metab 23:84–89

    Article  PubMed  CAS  Google Scholar 

  23. Khosla S, Melton LJIII, Atkinson EJ, O’Fallon WM, Klee GG, Riggs BL (1998) Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 83:2266–2274

    Article  PubMed  CAS  Google Scholar 

  24. Ongphiphadhanakul B, Rajatanavin R, Chanprasertyothin S, Piaseu N, Chailurkit L (1998) Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males. Clin Endocrinol 49:803–809

    Article  CAS  Google Scholar 

  25. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM (1996) Reduced androgen receptor gene expression with first exon CAG repeat expression. Mol Endocrinol 10:1527–1535

    Article  PubMed  CAS  Google Scholar 

  26. Sandberg G, Schalling M (1997) Effect of in vivo promoter methylation and CGC repeat expansion on FMR-1 expression. Nucleic Acid Res 25:2883–2887

    Article  PubMed  CAS  Google Scholar 

  27. Simpson ER (2001) Role of aromatase in sex steroid action. J Mol Endocrinol 25:149–156

    Article  Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, University Hospital Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia

    Darko Kastelan, Ivana Kraljevic, Tina Dusek & Mirko Korsic

  2. Tissue Typing Centre, University Hospital Zagreb, Zagreb, Croatia

    Zorana Grubic, Katarina Stingl & Vesna Kerhin-Brkljacic

  3. Department of Medical Statistics, Epidemiology and Medical Informatics, Andrija Stampar School of Public Health, Zagreb, Croatia

    Ozren Polasek

Authors
  1. Darko Kastelan
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  2. Zorana Grubic
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  3. Ivana Kraljevic
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  4. Ozren Polasek
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  5. Tina Dusek
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  6. Katarina Stingl
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  7. Vesna Kerhin-Brkljacic
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  8. Mirko Korsic
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Correspondence to Darko Kastelan.

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Kastelan, D., Grubic, Z., Kraljevic, I. et al. The role of estrogen receptor-α gene TA polymorphism and aromatase gene TTTA polymorphism on peak bone mass attainment in males: is there an additive negative effect of certain allele combinations?. J Bone Miner Metab 27, 198–204 (2009). https://doi.org/10.1007/s00774-008-0029-3

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  • DOI: https://doi.org/10.1007/s00774-008-0029-3

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