Association of the T-cell Regulatory Ggene CTLA-4 with Suscep-tibility to Autoimmune Thyroid Disease in Population of Novosibirsk

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Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 (CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. The aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to graves’ disease (GD) and Hashimotos thyroiditis (HT). Materials and methods. We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 105 unrelated Novosibirsk patients with GD, in 101 patients with HT and 150 matched healthy subjects. Results. The distribution of genotype frequencies differed significantly between patients with GD and controls (p = 0.039). The allele G and the genotype GG were associated with the increased risk for GD (odds ratio OR = 1,55, 95% CI, 1,09—2,21, OR = 2,43, 95% CI, 1,17—5,01 respectively). In contrast, no differences in genotype frequencies were observed between HT patients and controls for the A(49)G exon 1 CTLA-4 gene polymorphism. Conclusion: This suggests that the CTLA-4 gene might play a role in the development of DTS in the Novosibirsk population.

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  1. Балаболкин М.И. Фундаментальная и клиническая тиреоидология: Руководство / Балаболкин М.И., Клебанова Е.М., Креминская В.М. М.: Медицина, 2007. 816 с.
  2. Дедов И.И. Эндокринология: Учебник / Дедов И.И., Мельничеко Г.А., Фадеев В.В.. М.: Медицина, 2000. 632 с.
  3. Савостьянов К.В., Чистяков Д.А., Петунина Н.А. и др. Генетическая предрасположенность к развитию диффузного токсического зоба в популяции Москвы // Пробл. эндокринол. 2004. Т. 50. № 6. С. 10-13.
  4. Chistyakov D.A., Savost’anov K.V., Turakulov R.I. et al. Complex association analysis of graves disease using a set of polymorphic markers // Mol. Genet. Metab. 2000. V. 70(3). P. 214-218.
  5. Cho H.J., Chung J.H., Kim I.S. et al. Lack of a genetic association between the CTLA-4 gene and Graves’ disease in Koreans // Thyroid. 2006. V. 16. P. 237-241.
  6. Hadj Kacem H., Bellassoued M., Bougacha-Elleuch N. et al. CTLA-4 gene polymorphisms in Tunisian patients with Graves’ disease // Clin. Immunol. 2001. V. 101(3). P. 361-365.
  7. Harper K., Balzano C., Rouvier E. et al. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location // J. Immun. 1991. V. 147. P. 1037-1044.
  8. Kinjo Y., Takasu N., Komiya I. et al. Remission of Graves’ hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene // J. Clin. Endocr. Metab. 2002. V. 87. P. 2593-2596.
  9. Kotsa K., Watson P.F., Weetman A.P. A CTLA-4 gene polymorphism is associated with both Graves’ disease and Hashimoto’s thyroiditis// Clin. Endocrinol. 1997. V. 46. P. 551-555.
  10. Kouki T., Gardine C. A., Yanagawa T., Degroot L.J. Relation of 3 Polymorphisms of the Ctla-4 Gene in Patients with Graves-Disease // J. Endocrinol. Investigat. 2002. V. 25. P. 208-213.
  11. Kouki T., Sawai Y., Gardine C.A. et al. CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease // J. Immun. 2000. V. 165. P. 6606-6611.
  12. Kristiansen O.P., Larsen Z.M., Pociot F. CTLA-4 in autoimmune diseases - a general susceptibility gene to autoimmunity? // Genes Immun. 2000. V. 1. P. 170-184.
  13. Linsley P.S., Nadler S.G., Bajorath J. et al. Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4): a disulfide-linked homodimer binds two CD86 molecules // J. Biol. Chem. 1995. V. 270. P. 15417-15424.
  14. Magistrelli G., Jeannin P., Herbault N. et al. A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells // Europ. J. Immun. 1999. V. 29. P. 3596-3602.
  15. Nithiyananthan R., Heward J.M., Allahabadia A. et al. Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom // Thyroid. 2002. V. 12(1). P. 3-6.
  16. Oaks M.K., Hallett K.M. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease // J. Immun. 2000. V. 164. P. 5015-5018.
  17. Park Y.J., Chung H.K., Park D.J. et al. Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans // Thyroid. 2000. V. 10(6). Р 453-459.
  18. Petrone A., Giorgi G., Mesturino C.A. et al. Association of DRB1*04-DQB1*0301 haplotype and lack of association of two polymorphic sites at CTLA-4 gene with Hashimoto’s thyroiditis in an Italian population // Thyroid. 2001. V. 11(2). P. 171-175.
  19. Sahin M., Erdogan M.F., Erdogan G. Cytotoxic. T lymphocyte-associated molecule-4 polymorphisms in Turkish Graves’ disease patients and association with probability of remission after antithyroid therapy // Eur. J. Intern. Med. 2005. V. 16 (5). P. 352-355.
  20. Bednarczuk T., Hiromatsu Y., Fukutani T. et al. Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves’ ophthalmopathy in European and Japanese populations // Eur. J. Endocrinol. 2003. V. 148. P. 13-18.
  21. Tomer Y., Barbesino G., Greenberg D.A. et al. Mapping the major susceptibility loci for familial Graves’ and Hashimoto’s diseases: Evidence for genetic heterogeneity and gene interactions // J. Clin. Endocrinol. Metab. 1999. V. 84. P. 4656-4664.
  22. Tomer Y., Greenberg D.A., Barbesino G. et al. CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production // J. Clin. Endocr. Metab. 2001. V. 86. P. 1687-1693.
  23. Ueda H., Howson J.M., Esposito L. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease // Nature. 2003. V. 423. P. 506-511.
  24. Vaidya B., Imrie H., Perros P. et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy // Lancet. 1999. V. 354. P. 743-744.



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