Advertisement

Endocrine

, Volume 45, Issue 3, pp 487–496 | Cite as

The exon 3 polymorphism of the growth hormone receptor is a severity-related factor for osteoporosis

  • Felipe Albuquerque Marques
  • Túlio Cesar Lins
  • Ricardo Moreno Lima
  • Rômulo Maia Carlos Fonseca
  • Nanci Maria de França
  • Ricardo Jacó de Oliveira
  • Maria Teresinha de Oliveira Cardoso
  • Rinaldo Wellerson Pereira
  • Robert PogueEmail author
Original Article

Abstract

The purpose of this study was to investigate the association between the GHR exon 3 fl/d3 polymorphism and body composition traits in Brazilian cohorts of normal post-menarche adolescent girls and in post-menopausal women with and without osteoporosis. First, multiplex PCR and quantitative PCR (TaqMan) were used with 105 DNA samples from the general Brazilian population to validate the SNP rs6873545 as a surrogate marker for the GHR polymorphism. Subsequently, genotyping was carried out to evaluate associations for this polymorphism in 136 post-menarche adolescents and 175 post-menopausal women, who were evaluated for body composition traits such as bone mineral density and fat-free mass. Statistical analysis used an independent sample t test, one-way ANOVA test and post hoc Tukey HSD test. Significant values were assumed by p < 0.05. Genotyping indicated complete linkage disequilibrium between the GHR polymorphism and the SNP alleles (r 2 = 1.0). Adolescents and healthy post-menopausal women showed no genotype associations for body composition traits or osteoporosis. However, a lower total body bone mineral density was observed in fl/fl post-menopausal women with osteoporosis (p = 0.0004). These results suggest that the SNP rs6873545 can be used as a surrogate for the GHR fl/d3 polymorphism due to linkage disequilibrium in the Brazilian population and that the fl/fl genotype is a severity–related risk factor for osteoporosis, but did not appear to be associated with disease status.

Keywords

Growth hormone receptor Polymorphism Growth Fat-free mass Bone mineral density Osteoporosis 

Notes

Acknowledgments

This work was supported, in part, by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq:MCT/CNPq-02/2006-Universal-475438/2006-0), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and by the Fundação de Apoio à Pesquisa do Distrito Federal (FAP-DF).

Ethical standards

All individuals, or their legal representatives, signed an informed consent allowing the use of their DNA for research purposes. The research protocol was approved by the Institutional Ethics Committee.

Conflict of interest

None.

Supplementary material

12020_2013_4_MOESM1_ESM.pdf (306 kb)
Supplementary material 1 (PDF 305 kb)

References

  1. 1.
    D.L. Duren, M. Seselj, A.W. Froehle, R.W. Nahhas, R.J. Sherwood, Skeletal growth and the changing genetic landscape during childhood and adulthood. Am. J. Phys. Anthropol. 150, 48–57 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    M.B. Davidson, Effect of growth hormone on carbohydrate and lipid metabolism. Endocr. Rev. 8, 115–131 (1987)PubMedCrossRefGoogle Scholar
  3. 3.
    J.P. Monson, W.M. Drake, P.V. Carroll, J.U. Weaver, J. Rodriguez-Arnao, M.O. Savage, Influence of growth hormone on accretion of bone mass. Horm. Res. 58(Suppl. 1), 52–56 (2002)PubMedCrossRefGoogle Scholar
  4. 4.
    A.A. Butler, D. Le Roith, Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu. Rev. Physiol. 63, 141–164 (2001)PubMedCrossRefGoogle Scholar
  5. 5.
    F. Lupu, J.D. Terwilliger, K. Lee, G.V. Segre, A. Efstratiadis, Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001)PubMedCrossRefGoogle Scholar
  6. 6.
    C. Ohlsson, B.A. Bengtsson, O.G. Isaksson, T.T. Andreassen, M.C. Slootweg, Growth hormone and bone. Endocr. Rev. 19, 55–79 (1998)PubMedGoogle Scholar
  7. 7.
    T. Ueland, Bone metabolism in relation to alterations in systemic growth hormone. Growth Horm. IGF Res. 14, 40–417 (2004)CrossRefGoogle Scholar
  8. 8.
    A. Giustina, G. Mazziotti, E. Canalis, Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535–559 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    J.P. Bonjour, G. Theintz, F. Law, D. Slosman, R. Rizzoli, Peak bone mass. Osteoporos. Int. 4(Suppl. 1), 7–13 (1994)PubMedCrossRefGoogle Scholar
  10. 10.
    S.J. Holmes, G. Economou, R.W. Whitehouse, J.E. Adams, S.M. Shalet, Reduced bone mineral density in patients with adult onset growth hormone deficiency. J. Clin. Endocrinol. Metab. 78, 669–674 (1994)PubMedGoogle Scholar
  11. 11.
    G. Johannsson, P. Marin, L. Lonn, M. Ottosson, K. Stenlof, P. Bjorntorp, L. Sjostrom, B.A. Bengtsson, Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J. Clin. Endocrinol. Metab. 82, 727–734 (1997)PubMedGoogle Scholar
  12. 12.
    J. Pantel, K. Machinis, M.L. Sobrier, P. Duquesnoy, M. Goossens, S. Amselem, Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J. Biol. Chem. 275, 18664–18669 (2000)PubMedCrossRefGoogle Scholar
  13. 13.
    G. Binder, F. Baur, R. Schweizer, M.B. Ranke, The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J. Clin. Endocrinol. Metab. 91, 659–664 (2006)PubMedCrossRefGoogle Scholar
  14. 14.
    A.A. Jorge, F.G. Marchisotti, L.R. Montenegro, L.R. Carvalho, B.B. Mendonca, I.J. Arnhold, Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency. J. Clin. Endocrinol. Metab. 91, 1076–1080 (2006)PubMedCrossRefGoogle Scholar
  15. 15.
    C. Dos Santos, L. Essioux, C. Teinturier, M. Tauber, V. Goffin, V. Bougnères, A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat. Genet. 36, 720–724 (2004)PubMedCrossRefGoogle Scholar
  16. 16.
    M.J. Wassenaar, O.M. Dekkers, A.M. Pereira, J.M. Wit, J.W. Smit, N.R. Biermasz, J.A. Romijn, Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 94, 3721–3730 (2009)PubMedCrossRefGoogle Scholar
  17. 17.
    A. Pilotta, P. Mella, M. Filisetti, B. Felappi, E. Prandi, G. Parrinello, L.D. Notarangelo, F. Buzi, Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children. J. Clin. Endocrinol. Metab. 91, 1178–1180 (2006)PubMedCrossRefGoogle Scholar
  18. 18.
    W.F. Blum, K. Machinis, E.P. Shavrikova, A. Keller, H. Stobbe, R.W. Pfaeffle, S. Amselem, The growth response to growth hormone (GH) treatment in children with isolated GH deficiency is independent of the presence of the exon 3-minus isoform of the GH receptor. J. Clin. Endocrinol. Metab. 91, 4171–4174 (2006)PubMedCrossRefGoogle Scholar
  19. 19.
    G. Lettre, J.L. Butler, K.G. Ardlie, J.N. Hirschhorn, Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation. Hum. Genet. 122, 129–139 (2007)PubMedCrossRefGoogle Scholar
  20. 20.
    N.A. Rosenberg, M. Nordborg, A general population-genetic model for the production by population structure of spurious genotype-phenotype associations in discrete, admixed or spatially distributed populations. Genetics 173, 1665–1678 (2006)PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    T.C. Lins, R.G. Vieira, B.S. Abreu, D. Grattapaglia, R.W. Pereira, Genetic composition of Brazilian population samples based on a set of twenty-eight ancestry informative SNPs. Am. J. Hum. Biol. 22, 187–192 (2010)PubMedGoogle Scholar
  22. 22.
    R.M. Fonseca, N.M. de Franca, R.W. Pereira, Suggestive linkage to chromosome 1q for bone mineral apparent density in Brazilian sister adolescents. Joint Bone Spine 79, 256–261 (2011)PubMedCrossRefGoogle Scholar
  23. 23.
    R. Moreno Lima, B.S. de Abreu, P. Gentil, T.C. de Lima Lins, D.R. Grattapaglia, R.W. Pereira, R.J. de Oliveira, Lack of association between vitamin D receptor genotypes and haplotypes with fat-free mass in postmenopausal Brazilian Women. J. Gerontol. 62, 966–972 (2007)CrossRefGoogle Scholar
  24. 24.
    P. Gentil, R.M. Lima, T.C. Lins, B.S. Abreu, R.W. Pereira, R.J. Oliveira, Physical activity, Cdx-2 genotype, and BMD. Int. J. Sports Med. 28, 1065–1069 (2007)PubMedCrossRefGoogle Scholar
  25. 25.
    J.A. Kanis, Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359, 1929–1936 (2002)PubMedCrossRefGoogle Scholar
  26. 26.
    WHO: Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. World Health Organ Technical Report Series, vol. 843, pp. 1–129 (1994)Google Scholar
  27. 27.
    C.A. Glad, G. Johannsson, L.M. Carlsson, P.A. Svensson, Rapid and high throughput genotyping of the growth hormone receptor exon 3 deleted/full-length polymorphism using a tagSNP. Growth Horm. IGF Res. 20, 270–273 (2010)PubMedCrossRefGoogle Scholar
  28. 28.
    J.D. Veldhuis, J.N. Roemmich, E.J. Richmond, A.D. Rogol, J.C. Lovejoy, M. Sheffield-Moore, N. Mauras, C.Y. Bowers, Endocrine control of body composition in infancy, childhood, and puberty. Endocr. Rev. 26, 114–146 (2005)PubMedCrossRefGoogle Scholar
  29. 29.
    Y. Fan, R.K. Menon, P. Cohen, D. Hwang, T. Clemens, D.J. DiGirolamo, J.J. Kopchick, D. Le Roith, M. Trucco, M.A. Sperling, Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J. Biol. Chem. 284, 19937–19944 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    E. Ziv, E.G. Burchard, Human population structure and genetic association studies. Pharmacogenomics 4, 431–441 (2003)PubMedCrossRefGoogle Scholar
  31. 31.
    R.P. Heaney, S. Abrams, B. Dawson-Hughes, A. Looker, R. Marcus, V. Matkovic, C. Weaver, Peak bone mass. Osteoporos. Int. 11, 985–1009 (2000)PubMedCrossRefGoogle Scholar
  32. 32.
    K.Y. Tse, B.R. Macias, R.S. Meyer, A.R. Hargens, Heritability of bone density: regional and gender differences in monozygotic twins. J. Orthop. Res. 27, 150–154 (2009)PubMedCrossRefGoogle Scholar
  33. 33.
    G. Kenth, Z. Shao, D.E. Cole, C.G. Goodyer, Relationship of the human growth hormone receptor exon 3 genotype with final adult height and bone mineral density. J. Clin. Endocrinol. Metab. 92, 725–728 (2007)PubMedCrossRefGoogle Scholar
  34. 34.
    T. Sugimoto, H. Kaji, D. Nakaoka, M. Yamauchi, S. Yano, T. Sugishita, D.J. Baylink, S. Mohan, K. Chihara, Effect of low-dose of recombinant human growth hormone on bone metabolism in elderly women with osteoporosis. Eur. J. Endocrinol. 147, 339–348 (2002)PubMedCrossRefGoogle Scholar
  35. 35.
    H.B. Baum, B.M. Biller, J.S. Finkelstein, K.B. Cannistraro, D.S. Oppenhein, D.A. Schoenfeld, T.H. Michel, H. Wittink, A. Klibanski, Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann. Intern. Med. 125, 883–890 (1996)PubMedCrossRefGoogle Scholar
  36. 36.
    M. Elbornsson, G. Gotherstrom, C. Franco, B.A. Bengtsson, G. Johannsson, J. Svensson, Effects of 3-year GH replacement therapy on bone mineral density in younger and elderly adults with adult-onset GH deficiency. Eur. J. Endocrinol. 166, 181–189 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    A.A. van der Klaauw, T. van der Straaten, R. Baak-Pablo, N.R. Biermasz, H.J. Guchelaar, A.M. Pereira, J.W. Smit, J.A. Romijn, Influence of the d3-growth hormone (GH) receptor isoform on short-term and long-term treatment response to GH replacement in GH-deficient adults. J. Clin. Endocrinol. Metab. 93, 2828–2834 (2008)PubMedCrossRefGoogle Scholar
  38. 38.
    E.J. Barbosa, J. Palming, C.A. Glad, H. Filipsson, J. Koranyi, B.A. Bengtsson, L.M. Carlsson, C.L. Boguszewski, G. Johannsson, Influence of the exon 3-deleted/full-length growth hormone (GH) receptor polymorphism on the response to GH replacement therapy in adults with severe GH deficiency. J. Clin. Endocrinol. Metab. 94, 639–644 (2009)PubMedCrossRefGoogle Scholar
  39. 39.
    C. Giavoli, E. Ferrante, E. Profka, L. Olgiati, S. Bergamaschi, C.L. Ronchi, E. Verrua, M. Filopanti, E. Passeri, L. Montefusco, A.G. Lania, S. Corbetta, M. Arosio, B. Ambrosi, A. Spada, P. Beck-Peccoz, Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy. Eur. J. Endocrinol. 163, 361–368 (2010)PubMedCrossRefGoogle Scholar
  40. 40.
    S. Perrini, L. Laviola, M.C. Carreira, A. Cignarelli, A. Natalicchio, F. Giorgino, The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J. Endocrinol. 205, 201–210 (2010)PubMedCrossRefGoogle Scholar
  41. 41.
    N.J. Lanning, C. Carter-Su, Recent advances in growth hormone signaling. Rev. Endocr. Metab. Disord. 7, 225–235 (2006)PubMedCrossRefGoogle Scholar
  42. 42.
    E. Canalis, The fate of circulating osteoblasts. N. Engl. J. Med. 352(19), 2014–2016 (2005)PubMedCrossRefGoogle Scholar
  43. 43.
    M. Kassem, W. Blum, J. Ristelli, L. Mosekilde, E.F. Eriksen, Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro. Calcif. Tissue Int. 52, 222–226 (1993)PubMedCrossRefGoogle Scholar
  44. 44.
    E. Mrak, I. Villa, R. Lanzi, M. Losa, F. Guidobono, A. Rubinacci, Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells. J. Endocrinol. 192, 639–645 (2007)PubMedCrossRefGoogle Scholar
  45. 45.
    L.C. Hofbauer, S. Khosla, C.R. Dunstan, D.L. Lacey, W.J. Boyle, B.L. Riggs, The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J. Bone Miner. Res. 15, 2–12 (2000)PubMedCrossRefGoogle Scholar
  46. 46.
    L.S. Argetsinger, G.S. Campbell, X. Yang, B.A. Witthuhn, O. Silvennoinen, J.N. Ihle, C. Carter-Su, Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74, 237–244 (1993)PubMedCrossRefGoogle Scholar
  47. 47.
    V.J. Moyes, D.M. Walker, S. Owusu-Antwi, K.T. Maher, L. Metherell, S.A. Akker, J.P. Monson, A.J. Clark, W.M. Drake, d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults. Clin. Endocrinol. (Oxf) 72, 807–813 (2010)CrossRefGoogle Scholar
  48. 48.
    K. Leung, I.A. Rajkovic, E. Peters, I. Markus, J.J. Van Wyk, K.K. Ho, Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action. Endocrinology 137, 2694–2702 (1996)PubMedGoogle Scholar
  49. 49.
    L. Xian, X. Wu, L. Pang, M. Lou, C.J. Rosen, T. Qiu, J. Crane, F. Frassica, L. Zhang, J.P. Rodriguez, J. Xiaofeng, Y. Shoshana, X. Shouhong, E. Argiris, W. Mei, C. Xu, Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med. 18, 1095–1101 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    F. Schreiner, S. Stutte, P. Bartmann, B. Gohlke, J. Woelfle, Association of the growth hormone receptor d3-variant and catch-up growth of preterm infants with birth weight of less than 1500 grams. J. Clin. Endocrinol. Metab. 92, 4489–4493 (2007)PubMedCrossRefGoogle Scholar
  51. 51.
    L. Gao, Z. Zheng, L. Cao, S. Shen, Y. Yang, Z. Zhao, D. Zhi, R. Cheng, Z. Pei, Y. Yongfu, F. Luo, The growth hormone receptor (GHR) exon 3 polymorphism and its correlation with metabolic profiles in obese Chinese children. Pediatr. Diabetes 12, 429–434 (2011)PubMedCrossRefGoogle Scholar
  52. 52.
    S.W. Park, S.T. Lee, Y.B. Sohn, S.H. Kim, S.Y. Cho, A.R. Ko, S.T. Ji, J.Y. Kwon, S. Yeau, K.H. Paik, J.W. Kim, D.K. Jin, A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome. Am. J. Med. Genet. A 155A, 2970–2973 (2011)PubMedCrossRefGoogle Scholar
  53. 53.
    S. Kohler, O. Tschopp, L. Sze, M. Neidert, R.L. Bernays, K.S. Spanaus, P. Wiesli, C. Schmid. Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: Is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on “safe” GH cut-off values? GenCompEndocrinol. (2013)Google Scholar
  54. 54.
    M. Mercado, B. Gonzalez, C. Sandoval, Y. Esquenazi, F. Mier, G. Vargas, A.L. de losMonteros, E. Sosa, Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly. J. Clin. Endocrinol. Metab. 93(9), 3411–3415 (2008)PubMedCrossRefGoogle Scholar
  55. 55.
    P. Kamenicky, C. Dos Santos, C. Espinosa, S. Salenave, F. Galland, Y. Le Bouc, P. Maison, P. Bougneres, P. Chanson, D3 GH receptor polymorphism is not associated with IGF1 levels in untreated acromegaly. Eur. J. Endocrinol. 161(2), 231–235 (2009)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Felipe Albuquerque Marques
    • 1
  • Túlio Cesar Lins
    • 2
  • Ricardo Moreno Lima
    • 3
  • Rômulo Maia Carlos Fonseca
    • 3
  • Nanci Maria de França
    • 4
  • Ricardo Jacó de Oliveira
    • 3
  • Maria Teresinha de Oliveira Cardoso
    • 5
  • Rinaldo Wellerson Pereira
    • 1
    • 2
    • 4
  • Robert Pogue
    • 1
    Email author
  1. 1.Programa de Pós-Graduação em Ciências Genômicas e BiotecnologiaUniversidade Católica de BrasíliaBrasíliaBrazil
  2. 2.Programa de Pós-Graduação em Patologia MolecularUniversidade de BrasíliaBrasíliaBrazil
  3. 3.Faculdade de Educação FísicaUniversidade de BrasíliaBrasíliaBrazil
  4. 4.Programa de Pós Graduação em Educação FísicaUniversidade Católica de BrasíliaTaguatingaBrazil
  5. 5.Curso de MedicinaUniversidade Católica de BrasíliaTaguatingaBrazil

Personalised recommendations