Skip to main content

Advertisement

SpringerLink
Log in

Association and gene–gene interaction analyses for polymorphic variants in CTLA-4 and FOXP3 genes: role in susceptibility to autoimmune thyroid disease

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Polymorphic variants of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and forkhead box protein P3 (FOXP3) genes are implicated in dysregulated immune homeostasis and autoimmune disorders. We analyzed the association between CTLA-4 rs231775 and FOXP3 rs3761548, rs3761549 polymorphisms and predisposition to autoimmune thyroid disease (AITD), inclusive of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) in South-Indian population.

Methods

A total of 355 AITD subjects (comprising 275 HT and 80 GD) and 285 randomly selected age- and sex-matched control subjects were genotyped for the aforementioned polymorphisms by PCR-RFLP method.

Results

The rs231775 “G” allele was preponderant in HT and GD subjects when compared with controls and exerted a dominant influence on the susceptibility to HT (p = 0.009) and GD (p = 0.02), respectively. There was no allelic association of rs3761548 and rs3761549 polymorphisms with AITD susceptibility, albeit a significant difference in genotype distribution with respect to rs3761549. Haplotype analysis revealed an increased frequency of rs3761548 “C”–rs3761549 “T” in HT and GD subjects, thereby associating it with disease predisposition (p = 0.03). Epistatic interaction analysis by multifactor dimensionality reduction approach revealed redundancy between CTLA-4 and FOXP3 genes in influencing the susceptibility to AITD.

Conclusions

The genetic variation in CTLA-4 gene with reference to rs231775 polymorphism contributes to an increased predisposition to HT and GD. Also, in conjunction with FOXP3 gene variants it seems to influence the susceptibility to HT and GD respectively. The significance of these findings in combination with antithyroid antibody screening could plausibly contribute towards meticulous case-finding for effective treatment of HT and GD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. S.M. McLachlan, B. Rapoport, Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr. Rev. 35, 59–105 (2014). https://doi.org/10.1210/er.2013-1055

    Article  CAS  PubMed  Google Scholar 

  2. A.P. Weetman, Chronic autoimmune thyroiditis. in ed. by L.E. Braverman, R.D. Utiger, Werner and Ingbar’s The Thyroid (Lippincott Williams and Wilkins, Philadelphia, 2000), pp. 721–732

  3. C. Dejaco, C. Duftner, B. Grubeck-Loebenstein, M. Schirmer, Imbalance of regulatory T cells in human autoimmune diseases. Immunology 117, 289–300 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. A. Kitz, E. Singer, D. Hafler, Regulatory T cells: from discovery to autoimmunity. Cold Spring Harb. Perspect. Med. (2018). https://doi.org/10.1101/cshperspect.a029041.

  5. A.M. Pesenacker, L. Cook, M.K. Levings, The role of FOXP3 in autoimmunity. Curr. Opin. Immunol. 43, 16–23 (2016). https://doi.org/10.1016/j.coi.2016.07.004

    Article  CAS  PubMed  Google Scholar 

  6. T.H. Brix, K.O. Kyvik, K. Christensen, L. Hegedus, Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 86, 930–934 (2001)

    CAS  PubMed  Google Scholar 

  7. B. Vaidya, P. Kendall-Taylor, S.H. Pearce, The genetics of autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 87, 5385–5397 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. Y. Tomer, A. Huber, The etiology of autoimmune thyroid disease: a story of genes and environment. J. Autoimmun. 32, 231–239 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. H.J. Lee, C.W. Li, S.S. Hammerstad, M. Stefan, Y. Tomer, Immunogenetics of autoimmune thyroid diseases: a comprehensive review. J. Autoimmun. 64, 82–90 (2015). https://doi.org/10.1016/j.jaut.2015.07.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. R.S. Brown, A. Lombardi, A. Hasham, D.A. Greenberg, J. Gordon, E. Concepcion, S.S. Hammerstad, V. Lotay, W. Zhang, Y. Tomer, Genetic analysis in young-age-of-onset Graves’ disease reveals new susceptibility loci. J. Clin. Endocrinol. Metab. 99(7), E1387–E1391 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. B. Vaidya, H. Imrie, P. Perros, E.T. Young, W.F. Kelly, D. Carr, D.M. Large, A.D. Toft, M.I. McCarthy, P. Kendall-Taylor, S.H. Pearce, The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum. Mol. Genet. 8, 1195–1199 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. H. Ueda, J.M. Howson, L. Esposito, J. Heward, H. Snook et al.. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. E.M. Jacobson, Y. Tomer, The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future. J. Autoimmun. 28, 85–98 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. N. Verma, S.O. Burns, L.S.K. Walker, D.M. Sansom, Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin. Exp. Immunol. 190, 1–7 (2017). https://doi.org/10.1111/cei.12997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. T.L. Walunas, D.J. Lenschow, C.Y. Bakker, P.S. Linsley, G.J. Freeman, J.M. Greene, C.B. Thompson, J.A. Bluestone, CTLA-4 can function as a negative regulator of T-cell activation. Immunity 1, 405–413 (1994)

    Article  CAS  Google Scholar 

  16. A. Lombardi, F. Menconi, D. Greenberg, E. Concepcion, M. Leo, R. Rocchi, M. Marinó, M. Keddache, Y. Tomer, Dissecting the genetic susceptibility to Graves’ disease in a cohort of patients of Italian origin. Front. Endocrinol. (Lausanne) 7, 21 (2016)

    Article  Google Scholar 

  17. T. Yanagawa, Y. Hidaka, V. Guimaraes, M. Soliman, L.J. DeGroot, CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J. Clin. Endocrinol. Metab. 80, 41–45 (1995)

    CAS  PubMed  Google Scholar 

  18. L. Nisticò, R. Buzzetti, L.E. Pritchard, B. Van der Auwera, C. Giovannini, E. Bosi, M.T. Larrad, M.S. Rios, C.C. Chow, C.S. Cockram, K. Jacobs, C. Mijovic, S.C. Bain, A.H. Barnett, C.L. Vandewalle, F. Schuit, F.K. Gorus, R. Tosi, P. Pozzilli, J.A. Todd, The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum. Mol. Genet. 5, 1075–1080 (1996).

    Article  PubMed  Google Scholar 

  19. T. Yanagawa, M. Taniyama, S. Enomoto, K. Gomi, H. Maruyama, Y. Ban, T. Saruta, CTLA4 gene polymorphism confers susceptibility to Graves’ disease in Japanese. Thyroid 7, 843–846 (1997)

    Article  CAS  PubMed  Google Scholar 

  20. H. Donner, H. Rau, P.G. Walfish, J. Braun et al.. CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 82, 143–146 (1997)

    CAS  PubMed  Google Scholar 

  21. T. Awata, S. Kurihara, M. Iitaka, S. Takei et al.. Association of CTLA-4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves’ disease and Hashimoto’s thyroiditis) in the Japanese population. Diabetes 47, 128–129 (1998)

    Article  CAS  PubMed  Google Scholar 

  22. J.M. Heward, A. Allahabadia, M. Armitage, A. Hattersley, P.M. Dodson, K. Macleod, J. Carr-Smith, J. Daykin, A. Daly, M.C. Sheppard, R.L. Holder, A.H. Barnett, J.A. Franklyn, S.C. Gough, The development of Graves’ disease and the CTLA-4 gene on chromosome 2q33. J. Clin. Endocrinol. Metab. 84, 2398–2401 (1999)

    CAS  PubMed  Google Scholar 

  23. Y.J. Park, H.K. Chung, D.J. Park, W.B. Kim, S.W. Kim, J.J. Koh, B.Y. Cho, Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans. Thyroid 10, 453–459 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. H.J. Cho, J.H. Chung, I.S. Kim, H.J. Kim, S.H. Cho, C.S. Ki, J.W. Kim, Lack of a genetic association between the CTLA-4 gene and Graves’ disease in Koreans. Thyroid 16, 237–241 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. H. Hadj Kacem, M. Bellassoued, N. Bougacha-Elleuch, M. Abid, H. Ayadi, CTLA-4 gene polymorphisms in Tunisian patients with Graves’ disease. Clin. Immunol. 101, 361–365 (2001)

    Article  CAS  PubMed  Google Scholar 

  26. H. Donner, J. Braun, C. Seidl, H. Rau, R. Finke, M. Ventz, P.G. Walfish, K.H. Usadel, K. Badenhoop, Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto’s thyroiditis and Addison’s disease. J. Clin. Endocrinol. Metab. 82, 4130–4132 (1997)

    CAS  PubMed  Google Scholar 

  27. A. Petrone, G. Giorgi, C.A. Mesturino, M. Capizzi, I. Cascino, L. Nistico, J. Osborn, U. Di Mario, R. Buzzetti, 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 11, 171–175 (2001)

    Article  CAS  PubMed  Google Scholar 

  28. R. Nithiyananthan, J.M. Heward, A. Allahabadia, J.A. Franklyn, S.C. Gough, Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom. Thyroid 12, 3–6 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. P.L. Chen, C.S. Fann, C.C. Chang, I.L. Wu, W.Y. Chiu, C.Y. Lin, W.S. Yang, T.C. Chang, Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves’ disease in Han population of Taiwan. Genes Immun. 9, 87–92 (2008)

    Article  CAS  PubMed  Google Scholar 

  30. A. Bicek, K. Zaletel, S. Gaberscek, E. Pirnat, B. Krhin, T.G. Stopar, S. Hojker, 49A/G and CT60 polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4 gene associated with autoimmune thyroid disease. Hum. Immunol. 70, 820–824 (2009). https://doi.org/10.1016/j.humimm.2009.06.016

    Article  CAS  PubMed  Google Scholar 

  31. J. Yang, Q. Qin, N. Yan, Y.F. Zhu, C. Li, X.J. Yang, X. Wang, M. Pandey, P. Hou, J.A. Zhang, CD40 C/T(-1) and CTLA-4 A/G(49) SNPs are associated with autoimmune thyroid diseases in the Chinese population. Endocrine 41, 111–115 (2012). https://doi.org/10.1007/s12020-011-9510-1

    Article  CAS  PubMed  Google Scholar 

  32. M. Feng, F.B. Zhang, H.R. Deng, The CTLA4+ 49A/G polymorphism is associated with an increased risk of Hashimoto’s thyroiditis in Asian but not Caucasian populations: an updated meta-analysis. Endocrine 44, 350–358 (2013). https://doi.org/10.1007/s12020-013-0014-z

    Article  CAS  PubMed  Google Scholar 

  33. H.F. Hou, X. Jin, T. Sun, C. Li, B.F. Jiang, Q.W. Li, Cytotoxic T lymphocyte-associated antigen 4 gene polymorphisms and autoimmune thyroid diseases: an updated systematic review and cumulative meta-analysis. Int. J. Endocrinol. 747816 (2015). https://doi.org/10.1155/2015/747816

  34. C.J. Owen, J.A. Eden, C.E. Jennings, V. Wilson, T.D. Cheetham, S.H. Pearce, Genetic association studies of the FOXP3 gene in Graves’ disease and autoimmune Addison’s disease in the United Kingdom population. J. Mol. Endocrinol. 37, 97–104 (2006)

    Article  CAS  PubMed  Google Scholar 

  35. N. Inoue, M. Watanabe, M. Morita, R. Tomizawa, T. Akamizu, K. Tatsumi, Y. Hidaka, Y. Iwatani, Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases. Clin. Exp. Immunol. 162, 402–406 (2010). https://doi.org/10.1111/j.1365-2249.2010.04229.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Y. He, H. Na, Y. Li, Z. Qiu, W. Li, FoxP3 rs3761548 polymorphism predicts autoimmune disease susceptibility: a meta-analysis. Hum. Immunol. 74, 1665–1667 (2013). https://doi.org/10.1016/j.humimm.2013.08.270

    Article  CAS  PubMed  Google Scholar 

  37. A. Bossowski, H. Borysewicz-Sańczyk, N. Wawrusiewicz-Kurylonek, A. Zasim, M. Szalecki, B. Wikiera et al.. Analysis of chosen polymorphisms in FoxP3 gene in children and adolescents with autoimmune thyroid diseases. Autoimmunity 47, 395–400 (2014). https://doi.org/10.3109/08916934.2014.910767

    Article  CAS  PubMed  Google Scholar 

  38. L. Zheng, X. Wang, L. Xu, N. Wang, P. Cai, T. Liang, L. Hu, Foxp3 gene polymorphisms and haplotypes associate with susceptibility of Graves’ disease in Chinese Han population. Int. Immunopharmacol. 25, 425–431 (2015). https://doi.org/10.1016/j.intimp.2015.02.020

    Article  CAS  PubMed  Google Scholar 

  39. M.G. Lee, S.C. Bae, Y.H. Lee, Association between FOXP3 polymorphisms and susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 48(7), 445–452 (2015). https://doi.org/10.3109/08916934.2015.1045582

    Article  CAS  PubMed  Google Scholar 

  40. M. Yu, X. Tan, Y. Huang, FoxP3 variants are associated with susceptibility to Grave’s disease in Chinese population. Eur. J. Inflamm. 15(12), 113–119 (2017)

    Article  CAS  Google Scholar 

  41. E.A. Tivol, F. Borriello, A.N. Schweitzer, W.P. Lynch, J.A. Bluestone, A.H. Sharpe, Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction: revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995)

    Article  CAS  Google Scholar 

  42. S. Anjos, A. Nguyen, H. Ounissi-Benkalha, M.C. Tessier, C. Polychronakos, A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem. 277, 46478–46486 (2002)

    Article  CAS  PubMed  Google Scholar 

  43. P. Song, X.W. Wang, H.X. Li, K. Li, L. Liu, C. Wei, Z. Jian, X.L. Yi, Q. Li, G. Wang, C.Y. Li, T.W. Gao, Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population. Br. J. Dermatol. 169(3), 571–578 (2013)

    Article  CAS  PubMed  Google Scholar 

  44. L.W. Hahn, M.D. Ritchie, J.H. Moore, Multifactor dimensionality reduction software for detecting gene–gene and gene–environment interactions. Bioinformatics 19(3), 376–382 (2003)

    Article  CAS  PubMed  Google Scholar 

  45. H. Schneider, J. Downey, A. Smith, B.H. Zinselmeyer, C. Rush, J.M. Brewer, B. Wei, N. Hogg, P. Garside, C.E. Rudd, Reversal of the TCR stop signal by CTLA-4. Science 313, 1972–1975 (2006)

    Article  CAS  PubMed  Google Scholar 

  46. T. Kouki, Y. Sawai, C.A. Gardine, M.E. Fisfalen, M.L. Alegre, L.J. DeGroot, 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. Immunol. 165, 6606–6611 (2000)

    Article  CAS  PubMed  Google Scholar 

  47. T. Kouki, C.A. Gardine, T. Yanagawa, L.J. Degroot, Relation of three polymorphisms of the CTLA-4 gene in patients with Graves’ disease. J. Endocrinol. Invest. 25, 208–213 (2002)

    Article  CAS  PubMed  Google Scholar 

  48. S.X. Zhao, C.M. Pan, H.M. Cao et al.. Association of the CTLA4 gene with Graves’ disease in the Chinese Han population. PLoS ONE 5, e9821 (2010). https://doi.org/10.1371/journal.pone.0009821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. B. Vaidya, E.J. Oakes, H. Imrie, A.J. Dickinson, P. Perros, P. Kendall-Taylor, S.H. Pearce, CTLA4 gene and Graves’ disease: association of Graves’ disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clin. Endocrinol. (Oxf.) 58, 732–735 (2003)

    Article  CAS  Google Scholar 

  50. B. Jurecka-Lubieniecka, R. Ploski, D. Kula, A. Krol, T. Bednarczuk, Z. Kolosza, A. Tukiendorf, S. Szpak-Ulczok, A. Stanjek-Cichoracka, J. Polanska, B. Jarzab, Association between age at diagnosis of Graves’ disease and variants in genes involved in immune response. PLoS ONE 8, e59349 (2013). https://doi.org/10.1371/journal.pone.0059349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. E. Pawlak-Adamska, I. Frydecka, M. Bolanowski, A. Tomkiewicz et al.. CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves’ disease and modulates clinical phenotype of disease. Endocrine 55, 186–199 (2017). https://doi.org/10.1007/s12020-016-1096-1

    Article  CAS  PubMed  Google Scholar 

  52. K. Kotsa, P.F. Watson, A.P. Weetman, A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clin. Endocrinol. (Oxf.) 46, 551–554 (1997)

    Article  CAS  Google Scholar 

  53. H. Patel, M.S. Mansuri, M. Singh, R. Begum, M. Shastri, A. Misra, Association of cytotoxic T-lymphocyte antigen 4 (CTLA4) and thyroglobulin (TG) genetic variants with autoimmune hypothyroidism. PLoS One 11, e0149441 (2016). https://doi.org/10.1371/journal.pone.0149441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. S. Ramgopal, C. Rathika, M.R. Padma, V. Murali, K. Arun, M.N. Kamaludeen, K. Balakrishnan, Interaction of HLA-DRB1* alleles and CTLA4 (+49 AG) gene polymorphism in autoimmune thyroid disease. Gene 642, 430–438 (2018). https://doi.org/10.1016/j.gene.2017.11.057

    Article  CAS  PubMed  Google Scholar 

  55. F.K. Kavvoura, T. Akamizu, T. Awata, Y. Ban, D.A. Chistiakov et al.. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. J. Clin. Endocrinol. Metab. 92, 3162–3170 (2007)

    Article  CAS  PubMed  Google Scholar 

  56. S. Furqan, N.U. Haque, N. Islam, Conversion of autoimmune hypothyroidism to hyperthyroidism. BMC Res. Notes 7, 489 (2014). https://doi.org/10.1186/1756-0500-7-489

    Article  PubMed  PubMed Central  Google Scholar 

  57. H. Qiu, W. Tang, P. Yin, F. Cheng, L. Wang, Cytotoxic T-lymphocyte associated antigen 4 polymorphism and Hashimoto’s thyroiditis susceptibility: a meta-analysis. Endocrine 45, 198–205 (2014). https://doi.org/10.1007/s12020-013-9985-z.

    Article  CAS  PubMed  Google Scholar 

  58. Y. Hu, K. Xu, L. Jiang, L. Zhang, H. Shi, D. Cui, Associations between three CTLA-4 polymorphisms and Hashimoto’s thyroiditis risk: an updated meta-analysis with trial sequential analysis. Genet. Test. Mol. Biomark. 22, 224–236 (2018). https://doi.org/10.1089/gtmb.2017.0243.

    Article  CAS  Google Scholar 

  59. N. Inoue, M. Watanabe, H. Yamada, K. Takemura, F. Hayashi et al.. Associations between autoimmune thyroid disease prognosis and functional polymorphisms of susceptibility genes, CTLA4, PTPN22, CD40, FCRL3, and ZFAT, previously revealed in genome-wide association studies. J. Clin. Immunol. 32, 1243–1252 (2012). https://doi.org/10.1007/s10875-012-9721-0

    Article  CAS  PubMed  Google Scholar 

  60. A.G. Unnikrishnan, S. Kalra, R.K. Sahay, G. Bantwal, M. John, N. Tewari, Prevalence of hypothyroidism in adults: an epidemiological study in eight cities of India. Indian J. Endocrinol. Metab. 17(4), 647–652 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. S.T. Ngo, F.J. Steyn, P.A. McCombe, Gender differences in autoimmune disease. Front. Neuroendocrinol. 35(3), 347–369 (2014)

    Article  CAS  PubMed  Google Scholar 

  62. N. Ishido, N. Inoue, M. Watanabe, Y. Hidaka, Y. Iwatani, The relationship between skewed X chromosome inactivation and the prognosis of Graves’ and Hashimoto’s diseases. Thyroid 25(2), 256–261 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. J. Daroszewski, E. Pawlak, L. Karabon, I. Frydecka, A. Jonkisz, M. Slowik, M. Bolanowski, Soluble CTLA-4 receptor an immunological marker of Graves’ disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms. Eur. J. Endocrinol. 161, 787–793 (2009)

    Article  CAS  PubMed  Google Scholar 

  64. H. Kimura, Y. Kato, S. Shimizu, K. Takano, K. Sato, Association of polymorphism at position 49 in exon 1 of the cytotoxic T-lymphocyte-associated factor 4 gene with Graves’ disease refractory to medical treatment, but not with amiodarone-associated thyroid dysfunction. Thyroid 19, 975–981 (2009). https://doi.org/10.1089/thy.2009.0066.

    Article  CAS  PubMed  Google Scholar 

  65. P.W. Wang, I.Y. Chen, R.T. Liu, C.J. Hsieh, E. Hsi, S.H. Juo, Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves’ disease relapse after antithyroid drug withdrawal: a follow-up study. J. Clin. Endocrinol. Metab. 92, 2513–2518 (2007)

    Article  CAS  PubMed  Google Scholar 

  66. S. Tanrikulu, Y. Erbil, E. Ademoglu, H. Işsever, U. Barbaros, F. Kutlutürk, S. Ozarmagan, S. Tezelman, The predictive value of CTLA-4 and Tg polymorphisms in the recurrence of Graves’ disease after antithyroid withdrawal. Endocrine 30, 377–381 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Nusrath Fathima would like to thank University Grants Commission (UGC)-India for providing financial support in the form of Maulana Azad National Fellowship to conduct the study. The authors thank the clinicians and management of Princess Esra Hospital for their assistance in this study. The authors are grateful to all the participants of the study.

Author information

Authors and Affiliations

  1. Department of Genetics, Osmania University, Hyderabad, Telangana, India

    Nusrath Fathima & Mohammed Ishaq

  2. Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, Telangana, India

    Parimala Narne

  3. Salar-E-Millat, Research Centre for Cellular and Molecular Medicine, Princess Esra Hospital, Deccan College of Medical Sciences, Hyderabad, Telangana, India

    Mohammed Ishaq

Authors
  1. Nusrath Fathima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Parimala Narne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed Ishaq
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Parimala Narne or Mohammed Ishaq.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fathima, N., Narne, P. & Ishaq, M. Association and gene–gene interaction analyses for polymorphic variants in CTLA-4 and FOXP3 genes: role in susceptibility to autoimmune thyroid disease. Endocrine 64, 591–604 (2019). https://doi.org/10.1007/s12020-019-01859-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-01859-3

Keywords

Search

Navigation