Calcified Tissue International

, Volume 73, Issue 3, pp 237–243 | Cite as

A CAG Repeat Polymorphism in the Androgen Receptor Gene is Associated with Reduced Bone Mass and Increased Risk of Osteoporotic Fractures

  • B. L. Langdahl
  • L. Stenkjær
  • M. Carstens
  • C. L. Tofteng
  • E. F. Eriksen
Clinical Investigations

Abstract

Osteoporosis is a common disease with a strong genetic component. Hypogonadism results in low bone mass and it increases significantly the risk of osteoporosis in both sexes. The estrogen and androgen receptor genes are therefore strong candidates for mediating the genetic influence on bone mass and risk of osteoporosis. A CAG repeat in the first exon of the androgen receptor (AR) is associated with reduced transcriptional activity of the AR. We therefore examined whether this CAG repeat polymorphism is associated with changes in bone mass and risk of osteoporotic fractures in 284 osteoporotic patients with vertebral fractures and 327 normal individuals. The number of CAG repeats varied between 13 and 30 in men and between 7 and 34 in women. The short and long alleles comprised 19.2 ± 2.5 and 19.0 ± 2.3 repeats (ns) and 22.7 ± 2.4 and 21.9 ± 2.4 (P < 0.01) in women with vertebral fractures and normal women, respectively. This difference was also reflected in the average number of CAG repeats: 21.0 ± 2.0 in osteoporotic women vs. 20.5 ± 2.0 in normal women (P < 0.05). 54.8% of women with osteoporotic fractures vs. 45.9% of normal women had average number of CAG repeats of 21 and more (χ2 = 3.11, P = 0.08). Logistic regression analyses revealed that both the average number of CAG repeats and the length of the long allele were significant predictors of osteoporotic fractures in women (P < 0.05 and P < 0.01, respectively). Men with vertebral fractures had 20.0 ± 2.8 CAG repeats compared with 20.7 ± 2.5 CAG repeats in normal men (ns). Linear regression analysis revealed that the length of the long allele was negatively correlated with BMD of the lumbar spine (P < 0.05) and femoral neck (P < 0.05) in women. In men, linear regression analyses demonstrated that BMD of the lumbar spine (P < 0.05), femoral neck (P < 0.05) and total hip (P < 0.05) was positively correlated with length of the CAG repeat polymorphism. In conclusion, we have demonstrated that the CAG repeat polymorphism in the first exon of the AR gene is associated with reduced bone mass and increased risk of osteoporotic fractures in women.

Keywords

Androgen receptor Osteoporosis Bone mass Polymorphism Bone turnover 

Notes

Acknowledgements

The authors thank The Novo Nordisk Fonden, The Institute of Experimental Clinical Research at University of Aarhus, The Fonden til Lægevidenskabens Fremme, and The Eli Lilly Research Foundation.

References

  1. 1.
    Pocock, NA, Eisman, JA, Hopper, JL, Yeates, MG, Sambrook, PN, Eberi, S 1987Genetic determinants of bone mass in adults.A twin study. J Clin Invest80706710Google Scholar
  2. 2.
    Slemenda, CW, Christian, JC, Williams, CJ, Norton, JA, Johnston, CC 1991Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates.J Bone Miner Res6561567PubMedGoogle Scholar
  3. 3.
    Soroko, SB, Barrett-Connor, E, Edelstein, SL, Kritz-Silverstein, D 1994Family history of osteoporosis and bone mineral density at the axial skeleton: the Rancho Bernardo Study.J Bone Miner Res9761769PubMedGoogle Scholar
  4. 4.
    Gueguen, R, Jouanny, P, Guillemin, F, Kuntz, C, Pourel, J, Siest, G 1995Segregation analysis and variance components analysis of bone mineral density in healthy families.J Bone Miner Res1020172022PubMedGoogle Scholar
  5. 5.
    Risch, N, Merikangas, K 1996The future of genetic studies of complex human diseases.Science27315161517PubMedGoogle Scholar
  6. 6.
    Langdahl, BL, Lokke, E, Carstens, M, Stenkjaer, LL, Eriksen, EF 2000A 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 Res1522222230PubMedGoogle Scholar
  7. 7.
    Albagha, OM, McGuigan, FE, Reid, DM, Ralston, SH 2001Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom.J Bone Miner Res16128134PubMedGoogle Scholar
  8. 8.
    Ongphiphadhanakul, B, Rajatanavin, R, Chanprasertyothin, S, Piaseu, N, Chailurkit, L, Sirisriro, R, Komindr, S 1998Estrogen receptor gene polymorphism is associated with bone mineral density in premenopausal women but not in postmenopausal women.J Endocrinol Invest21487493PubMedGoogle Scholar
  9. 9.
    Edwards, A, Hammond, HA, Jin, L, Caskey, CT, Chakraborty, R 1992Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups.Genomics12241253PubMedGoogle Scholar
  10. 10.
    Chamberlain, NL, Driver, ED, Miesfeld, RL 1994The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.Nucleic Acids Res2231813186PubMedGoogle Scholar
  11. 11.
    Kazemi-Esfarjani, P, Trifiro, MA, Pinsky, L 1995Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies.Hum Mol Genet4523527PubMedGoogle Scholar
  12. 12.
    Tut, TG, Ghadessy, FJ, Trifiro, MA, Pinsky, L, Yong, EL 1997Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility.J Clin Endocrinol Metab8237773782PubMedGoogle Scholar
  13. 13.
    Mhatre, AN, Trifiro, MA, Kaufman, M, Kazemi-Esfarjani, P, Figlewicz, D, Rouleau, G, Pinsky, L 1993Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy.Nat Genet5184188PubMedGoogle Scholar
  14. 14.
    Irvine, RA, Yu, MC, Ross, RK, Coetzee, GA 1995The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer.Cancer Res5519371940PubMedGoogle Scholar
  15. 15.
    Wallerand, H, Remy-Martin, A, Chabannes, E, Bermont, L, Adessi, G, Bittard, H 2001Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility.Fertil Steril76769774CrossRefPubMedGoogle Scholar
  16. 16.
    Dowsing, AT, Yong, EL, Clark, M, McLachlan, RI, de Kretser, DM, Trounson, AO 1999Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene [see comments].Lancet354640643CrossRefPubMedGoogle Scholar
  17. 17.
    Mitsumori, K, Terai, A, Oka, H, Segawa, T, Ogura, K, Yoshida, O, Ogawa, O 1999Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth.Prostate41253257PubMedGoogle Scholar
  18. 18.
    Modugno, F, Weissfeld, JL, Trump, DL, Zmuda, JM, Shea, P, Cauley, JA, Ferrell, RE 2001Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk.Clin Cancer Res730923096PubMedGoogle Scholar
  19. 19.
    Hardy, DO, Scher, HI, Bogenreider, T, Sabbatini, P, Zhang, ZF, Nanus, DM, Catterall, JF 1996Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset.J Clin Endocrinol Metab8144004405PubMedGoogle Scholar
  20. 20.
    Beilin, J, Harewood, L, Frydenberg, M, Mameghan, H, Martyres, RF, Farish, SJ, Yue, C, Deam, DR, Byron, KA, Zajac, JD 2001A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects.Cancer92941949CrossRefPubMedGoogle Scholar
  21. 21.
    Giovannucci, E, Stampfer, MJ, Krithivas, K, Brown, M, Dahl, D, Brufsky, A, Talcott, J, Hennekens, CH, Kantoff, PW 1997The CAG repeat within the androgen receptor gene and its relationship to prostate cancer.Proc Natl Acad Sci USA9433203323PubMedGoogle Scholar
  22. 22.
    Giwercman, YL, Xu, C, Arver, S, Pousette, A, Reneland, R 1998No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men.Clin Genet54435436PubMedGoogle Scholar
  23. 23.
    Miller, EA, Stanford, JL, Hsu, L, Noonan, E, Ostrander, EA 2001Polymorphic repeats in the androgen receptor gene in high-risk sibships.Prostate48200205PubMedGoogle Scholar
  24. 24.
    Bousema, JT, Bussemakers, MJ, van Houwelingen, KP, Debruyne, FM, Verbeek, AL, de La Rosette, JJ, Kiemeney, LA 2000Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia.Eur Urol37234238PubMedGoogle Scholar
  25. 25.
    Lange, EM, Chen, H, Brierley, K, Livermore, H, Wojno, KJ, Langefeld, CD, Lange, K, Cooney, KA 2000The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer.Cancer Epidemiol Biomarkers Prev9439442PubMedGoogle Scholar
  26. 26.
    Edwards, SM, Badzioch, MD, Minter, R,  et al. 1999Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival.Int J Cancer84458465PubMedGoogle Scholar
  27. 27.
    Latil, AG, Azzouzi, R, Cancel, GS, Guillaume, EC, Cochan-Priollet, B, Berthon, PL, Cussenot, O 2001Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.Cancer9211301137CrossRefPubMedGoogle Scholar
  28. 28.
    Yaron, M, Levy, T, Chetrit, A, Levavi, H, Sabah, G, Schneider, D, Halperin, R, Ben Rafael, Z, Friedman, E 2001The polymorphic CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma.Cancer9211901194CrossRefPubMedGoogle Scholar
  29. 29.
    Levine, DA, Boyd, J 2001The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series.Cancer Res61908911PubMedGoogle Scholar
  30. 30.
    Giguere, Y, Dewailly, E, Brisson, J, Ayotte, P, Laflamme, N, Demers, A, Forest, VI, Dodin, S, Robert, J, Rousseau, F 2001Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population.Cancer Res6158695874PubMedGoogle Scholar
  31. 31.
    Yu, H, Bharaj, B, Vassilikos, EJ, Giai, M, Diamandis, EP 2000Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer.Breast Cancer Res Treat59153161CrossRefPubMedGoogle Scholar
  32. 32.
    Legro, RS, Shahbahrami, B, Lobo, RA, Kovacs, BW 1994Size polymorphisms of the androgen receptor among female Hispanics and correlation with androgenic characteristics.Obstet Gynecol83701706Google Scholar
  33. 33.
    Sowers, M, Willing, M, Burns, T, Deschenes, S, Hollis, B, Crutchfield, M, Jannausch, M 1999Genetic markers, bone mineral density, and serum osteocalcin levels.J Bone Miner Res1414111419PubMedGoogle Scholar
  34. 34.
    Zitzmann, M, Brune, M, Kornmann, B, Gromoll, J, Junker, R, Nieschlag, E 2001The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males.Clin Endocrinol (Oxf)55649657CrossRefGoogle Scholar
  35. 35.
    van Pottelbergh, I, Lumbroso, S, Goemaere, S, Sultan, C, Kaufman, JM 2001Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men.Clin Endocrinol (Oxf)55659666CrossRefGoogle Scholar
  36. 36.
    Salmen, T, Heikkinen, AM, Mahonen, A, Kroger, H, Komulainen, M, Pallonen, H, Saarikoski, S, Honkanen, R, Maenpaa, PH 2003Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial.J Bone Miner Res18319324PubMedGoogle Scholar
  37. 37.
    Dunning, AM, McBride, S, Gregory, J, Durocher, F, Foster, NA, Healey, CS, Smith, N, Pharoah, PD, Luben, RN, Easton, DF, Ponder, BA 1999No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer.Carcinogenesis2021312135CrossRefPubMedGoogle Scholar
  38. 38.
    Genant, HK, Grampp, S, Gluer, CC, Faulkner, KG, Jergas, M, Engelke, K, Hagiwara, S, Van Kuijk, C 1994Universal standardization for dual x-ray absorptiometry: patient and phantom cross-calibration results [see comments].J Bone Miner Res915031514PubMedGoogle Scholar
  39. 39.
    Risteli, J, Elomaa, I, Niemi, S, Novamo, A, Risteli, L 1993Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation.Clin Chem39635640PubMedGoogle Scholar
  40. 40.
    Nielsen, HK, Laurberg, P, Brixen, K, Mosekilde, L 1991Relations between diurnal variations in serum osteocalcin, cortisol, parathyroid hormone, and ionized calcium in normal individuals.Acta Endocrinol (Copenh)124391398Google Scholar
  41. 41.
    Kunkel, LM, Smith, KD, Boyer, SH, Borgaonkar, DS, Wachtel, SS, Miller, OJ, Breg, WR, Jones Jr, HW, Rary, JM 1977Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants.Proc Natl Acad Sci USA7412451249PubMedGoogle Scholar
  42. 42.
    Mori, K, Ushiyama, T, Inoue, K, Hukuda, S 2000Polymorphic CAG repeats of the androgen receptor gene in Japanese male patients with ankylosing spondylitis.Rheumatology.(Oxford)39530532CrossRefGoogle Scholar
  43. 43.
    Tanner, SM, Orstavik, KH, Kristiansen, M, Lev, D, Lerman-Sagie, T, Sadeh, M, Liechti-Gallati, S 1999Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother.Hum Genet104249253Google Scholar
  44. 44.
    Naumova, AK, Olien, L, Bird, LM, Smith, M, Verner, AE, Leppert, M, Morgan, K, Sapienza, C 1998Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human.Eur J Hum Genet6552562Google Scholar
  45. 45.
    Naumova, AK, Plenge, RM, Bird, LM, Leppert, M, Morgan, K, Willard, HF, Sapienza, C 1996Heritability of X chromosome—inactivation phenotype in a large family.Am J Hum Genet5811111119PubMedGoogle Scholar
  46. 46.
    Calvo, RM, Asuncion, M, Sancho, J, San Millan, JL, Escobar-Morreale, HF 2000The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism.J Clin Endocrinol Metab8517351740PubMedGoogle Scholar
  47. 47.
    Westberg, L, Baghaei, F, Rosmond, R, Hellstrand, M, Landen, M, Jansson, M, Holm, G, Bjomtorp, P, Eriksson, E 2001Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.J CIin Endocrinol Metab8625622568Google Scholar
  48. 48.
    Vanderschueren, D, van Herck, E, De Coster, R, Bouillon, R 1996Aromatization of androgens is important for skeletal maintenance of aged male rats.Calcif tissue Int59179183CrossRefPubMedGoogle Scholar
  49. 49.
    Vanderschueren, D, van Herck, E, Nijs, J, Ederveen, AG, De Coster, R, Bouillon, R 1997Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats.Endocrinology13823012307PubMedGoogle Scholar
  50. 50.
    Krithivas, K, Yurgalevitch, SM, Mohr, BA, Wilcox, CJ, Batter, SJ, Brown, M, Longcope, C, McKinlay, JB, Kantoff, PW 1999Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men.J Endocrinol162137142PubMedGoogle Scholar
  51. 51.
    Kawasaki, T, Ushiyama, T, Ueyama, H, Inoue, K, Mori, K, Ohkubo, I, Hukuda, S 1999Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis.Ann Rheum Dis58500502PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • B. L. Langdahl
    • 1
  • L. Stenkjær
    • 1
  • M. Carstens
    • 1
  • C. L. Tofteng
    • 2
  • E. F. Eriksen
    • 1
  1. 1.Department of Endocrinology and MetabolismAarhus University Hospital, Aarhus Amtssygehus, DK-8000 AarhusDenmark
  2. 2.Osteoporosis Research Clinic, Department of EndocrinologyHvidovre Hospital, DK-2650 HvidovreDenmark

Personalised recommendations