Horm Metab Res 2009; 41(6): 430-435
DOI: 10.1055/s-0029-1220902
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

The T393C Polymorphism of the Gαs Gene (GNAS1) is Associated with the Course of Graves' Disease

D. Glowacka 1 , C. Loesch 2 , K. T. M. Johnson 1 , K. Mann 3 , J. Esser 1 , N. G. Morgenthaler 4 , W. Siffert 5 , K. W. Schmid 6 , A. K. Eckstein 1
  • 1Department of Ophthalmology, University Hospital of Essen, University of Duisburg-Essen, Germany
  • 2Institute of Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Germany
  • 3Department of Medicine, University Hospital of Essen, Division of Endocrinology, University of Duisburg-Essen, Germany
  • 4Institut für Experimentelle Endokrinologie und Endokrinologisches Forschungszentrum EnForCé, Charité, Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
  • 5Institute of Pharmacogenetics, University Hospital of Essen, University of Duisburg-Essen, Germany
  • 6Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Germany
Further Information

Publication History

received 13.02.2009

accepted 20.04.2009

Publication Date:
09 June 2009 (online)

Abstract

Genotypes of the T393C SNP of GNAS1, a gene that encodes for the Gαs subunit of G proteins have been significantly associated with the clinical course in a variety of cancers. Since this SNP may also influence the course of Graves’ disease (GD) and, especially, Graves’ ophthalmopathy (GO), we determined genotype and allele frequency in a series of 359 patients, which were referred to our clinic within 6 months of the onset of GO. Among them, 336 patients also suffered from associated hyperthyroidism. Data on relapse and remission rates 12 months after termination of a 1 year antithyroid drug therapy was available for 276 patients. As controls, 820 healthy individuals were recruited. Our data suggest that the T393C SNP does not represent a risk factor for the development of both GD and GO. It was, however, significantly associated with the course of hyperthyroidism (p=0.013) and a similar trend was evident for the course of GO (p=0.093). Homozygous TT carriers showed a significantly increased risk (p=0.03) for hyperthyroidism to relapse (OR 2.4; 95% CI 1.1–5.4). Also, the TT genotype was associated with significantly increased serum TRAb levels (CC+CT: 5.4 IU/l vs. TT: 9.3 IU/l). This is probably caused by increased G-Protein susceptibility to TSHR-mediated stimulation through TRAb. Genotyping of the T393C SNP of GNAS1 may become a useful additional tool to predict the clinical course of GD and GO. This may allow the clinician to identify patients at risk for more severe courses of disease and to come to more timely decisions for treatment.

References

  • 1 Neer EJ. Heterotrimeric G proteins: organizers of transmembrane signals.  Cell. 1995;  80 249-257
  • 2 Wettschureck N, Offermanns S. Mammalian G proteins and their cell type specific functions.  Physiol Rev. 2005;  85 1159-1204
  • 3 Lania AG, Mantovani G, Spada A. Mechanisms of disease: Mutations of G proteins and G-protein-coupled receptors in endocrine diseases.  Nat Clin Pract Endocrinol Metab. 2006;  2 681-693
  • 4 Lehnerdt GF, Franz P, Winterhoff S, Bankfalvi A, Grehl S, Lang S, Schmid KW, Siffert W, Jahnke K, Frey UH. The GNAS1 T393C polymorphism predicts survival in patients with advanced squamous cell carcinoma of the larynx.  Laryngoscope. 2008;  118 2172-2176
  • 5 Schmitz KJ, Lang H, Frey UH, Sotiropoulos GC, Wohlschlaeger J, Reis H, Takeda A, Siffert W, Schmid KW, Baba HA. GNAS1 T393C polymorphism is associated with clinical course in patients with intrahepatic cholangiocarcinoma.  Neoplasia. 2007;  9 159-165
  • 6 Otterbach F, Callies R, Frey UH, Schmitz KJ, Wreczycki C, Kimmig R, Siffert W, Schmid KW. The T393C polymorphism in the gene GNAS1 of G protein is associated with survival of patients with invasive breast carcinoma.  Breast Cancer Res Treat. 2007;  105 311-317
  • 7 Frey UH, Lummen G, Jager T, Jockel KH, Schmid KW, Rubben H, Muller N, Siffert W, Eisenhardt A. The GNAS1 T393C polymorphism predicts survival in patients with clear cell renal cell carcinoma.  Clin Cancer Res. 2006;  12 ((3 Pt 1)) 759-763
  • 8 Frey UH, Nuckel H, Sellmann L, Siemer D, Kuppers R, Durig J, Duhrsen U, Siffert W. The GNAS1 T393C polymorphism is associated with disease progression and survival in chronic lymphocytic leukemia.  Clin Cancer Res. 2006;  12 5686-5692
  • 9 Frey UH, Eisenhardt A, Lummen G, Rubben H, Jockel KH, Schmid KW, Siffert W. The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.  Cancer Epidemiol Biomarkers Prev. 2005;  14 871-877
  • 10 Frey UH, Alakus H, Wohlschlaeger J, Schmitz KJ, Winde G, van Calker HG, Jockel KH, Siffert W, Schmid KW. GNAS1 T393C polymorphism and survival in patients with sporadic colorectal cancer.  Clin Cancer Res. 2005;  11 5071-5077
  • 11 Smith TJ, Tsai CC, Shih MJ, Tsui S, Chen B, Han R, Naik V, King CS, Press C, Kamat S, Goldberg RA, Phipps RP, Douglas RS, Gianoukakis AG. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy.  Thyroid. 2008;  18 983-988
  • 12 Weetman AP. The mechanisms of autoimmunity in endocrinology: application to the thyroid gland.  Ann Endocrinol (Paris). 2003;  64 26-27
  • 13 Weetman AP. Graves’ disease.  N Engl J Med. 2000;  343 1236-1248
  • 14 Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy.  Thyroid. 2002;  12 855-860
  • 15 Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. Chronology of Graves’ ophthalmopathy in an incidence cohort.  Am J Ophthalmol. 1996;  121 426-434
  • 16 Khoo DH, Ho SC, Seah LL, Fong KS, Tai ES, Chee SP, Eng PH, Aw SE, Fok AC. The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves’ disease identifies a group at markedly increased risk of ophthalmopathy.  Thyroid. 1999;  9 1175-1180
  • 17 Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF. Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy.  Clin Endocrinol (Oxf). 2000;  52 267-271
  • 18 Eckstein AK, Plicht M, Lax H, Hirche H, Quadbeck B, Mann K, Steuhl KP, Esser J, Morgenthaler NG. Clinical results of anti-inflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies.  Clin Endocrinol (Oxf). 2004;  61 612-618
  • 19 Eckstein AK, Plicht M, Lax H, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease.  J Clin Endocrinol Metab. 2006;  91 3464-3470
  • 20 Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy.  Clin Endocrinol (Oxf). 1997;  47 9-14
  • 21 Siffert W, Forster P, Jöckel KH, Mvere DA, Brinkmann B, Naber C, Crookes R, Du Heyns PA, Epplen JT, Fridey J, Freedman BI, Müller N, Stolke D, Sharma AM, Al Moutaery K, Grosse-Wilde H, Buerbaum B, Ehrlich T, Ahmad HR, Horsthemke B, Du Toit ED, Tiilikainen A, Ge J, Wang Y, Yang D, Hüsing J, Rosskopf D. Worldwide ethnic distribution of the G protein beta3 subunit 825 T allele and its association with obesity in Caucasian, Chinese, and Black African individuals.  J Am Soc Nephrol. 1999;  10 1921-1930
  • 22 Costagliola S, Morgenthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglohner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G, Usadel KH. Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease.  J Clin Endocrinol Metab. 1999;  84 90-97
  • 23 Schott M, Feldkamp J, Bathan C, Fritzen R, Scherbaum WA, Seissler J. Detecting TSH-receptor antibodies with the recombinant TBII assay: technical and clinical evaluation.  Horm Metab Res. 2000;  32 429-435
  • 24 Manji N, Carr-Smith JD, Boelaert K, Allahabadia A, Armitage M, Chatterjee VK, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.  J Clin Endocrinol Metab. 2006;  91 4873-4880
  • 25 Brix TH, Kyvik KO, Christensen K, Hegedus L. Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts.  J Clin Endocrinol Metab. 2001;  86 930-934
  • 26 Schott M, Eckstein AK, Willenberg HS, Nguyen TB, Morgenthaler NG, Scherbaum WA. Improved prediction of relapse of Graves’ thyrotoxicosis by combined determination of TSH receptor and thyroperoxidase antibodies.  Horm Metab Res. 2007;  39 5661
  • 27 Schott M, Morgenthaler NG, Fritzen R, Feldkamp J, Willenberg HS, Scherbaum WA, Seissler J. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease.  Horm Metab Res. 2004;  36 92-96
  • 28 Quadbeck B, Hoermann R, Hahn S, Roggenbuck U, Mann K, Janssen OE. Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor as predictors of relapse of Graves’ disease after withdrawal of antithyroid treatment.  Horm Metab Res. 2005;  37 745-750
  • 29 Orgiazzi J, Madec AM. Reduction of the risk of relapse after withdrawal of medical therapy for Graves’ disease.  Thyroid. 2002;  12 849-853
  • 30 Eckstein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J, Morgenthaler NG. Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.  Clin Endocrinol (Oxf). 2007;  67 607-612
  • 31 Liu J, Litman D, Rosenberg MJ, Yu S, Biesecker LG, Weinstein LS. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.  J Clin Invest. 2000;  106 1167-1174
  • 32 Liu J, Nealon JG, Weinstein LS. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB.  Hum Mol Genet. 2005;  14 95-102
  • 33 Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A. The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads.  J Clin Endocrinol Metab. 2002;  87 4736-4740
  • 34 Benker G, Kotulla P, Kendall-Taylor P, Emrich D, Reinwein D. TSH binding-inhibiting antibodies in hyperthyroidism: relationship to clinical signs and hormone levels.  Clin Endocrinol (Oxf). 1989;  30 19-28
  • 35 Bahn RS. TSH receptor expression in orbital tissue and its role in the pathogenesis of Graves’ ophthalmopathy.  J Endocrinol Invest. 2004;  27 216-220
  • 36 Crisp M, Starkey KJ, ane C, Ham J, Ludgate M. Adipogenesis in thyroid eye disease.  Invest Ophthalmol Vis Sci. 2000;  41 3249-3255
  • 37 Kumar S, Coenen MJ, Scherer PE, Bahn RS. Evidence for enhanced adipogenesis in the orbits of patients with Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 2004;  89 930-935
  • 38 Jacobson DH, Gorman CA. Diagnosis and management of endocrine ophthalmopathy.  Med Clin North Am. 1985;  69 973-988
  • 39 Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients.  Clin Endocrinol (Oxf). 2003;  58 280-287
  • 40 Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathway.  J Immunol. 2003;  170 6348-6354
  • 41 Douglas RS, Gianoukakis AG, Kamat S, Smith TJ. Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves’ disease may carry functional consequences for disease pathogenesis.  J Immunol. 2007;  178 3281-3287
  • 42 Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from patients with Graves’ disease induce the expression of T cell chemoattractants in their fibroblasts.  J Immunol. 2002;  168 942-950

Correspondence

A. K. EcksteinMD 

Department of Ophthalmology

University Hospital of Essen

Hufelandstraße 55

45122 Essen

Germany

Phone: +49/201/723 29 07

Fax: +49/201/723 56 41

Email: anja.eckstein@uk-essen.de

    >