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01.04.2014 | Original Article

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

verfasst von: 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 Pogue

Erschienen in: Endocrine | Ausgabe 3/2014

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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.

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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)PubMedCentralPubMedCrossRef

M.B. Davidson, Effect of growth hormone on carbohydrate and lipid metabolism. Endocr. Rev. 8, 115–131 (1987)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

C. Ohlsson, B.A. Bengtsson, O.G. Isaksson, T.T. Andreassen, M.C. Slootweg, Growth hormone and bone. Endocr. Rev. 19, 55–79 (1998)PubMed

T. Ueland, Bone metabolism in relation to alterations in systemic growth hormone. Growth Horm. IGF Res. 14, 40–417 (2004)CrossRef

A. Giustina, G. Mazziotti, E. Canalis, Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535–559 (2008)PubMedCentralPubMedCrossRef

J.P. Bonjour, G. Theintz, F. Law, D. Slosman, R. Rizzoli, Peak bone mass. Osteoporos. Int. 4(Suppl. 1), 7–13 (1994)PubMedCrossRef

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)PubMed

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)PubMed

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCentralPubMedCrossRef

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)PubMed

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)PubMedCrossRef

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)CrossRef

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)PubMedCrossRef

25.

J.A. Kanis, Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359, 1929–1936 (2002)PubMedCrossRef

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)

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCentralPubMedCrossRef

30.

E. Ziv, E.G. Burchard, Human population structure and genetic association studies. Pharmacogenomics 4, 431–441 (2003)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCentralPubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

41.

N.J. Lanning, C. Carter-Su, Recent advances in growth hormone signaling. Rev. Endocr. Metab. Disord. 7, 225–235 (2006)PubMedCrossRef

42.

E. Canalis, The fate of circulating osteoblasts. N. Engl. J. Med. 352(19), 2014–2016 (2005)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)CrossRef

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)PubMed

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)PubMedCentralPubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)PubMedCrossRef

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)

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)PubMedCrossRef

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)PubMedCrossRef

Titel: The exon 3 polymorphism of the growth hormone receptor is a severity-related factor for osteoporosis
verfasst von: 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 Pogue
Publikationsdatum: 01.04.2014
Verlag: Springer US
Erschienen in: Endocrine / Ausgabe 3/2014
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-013-0004-1

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