Abstract
Autoimmune thyroid diseases frequently overlaps with rheumatoid arthritis (RA). Among genetic factors, the role of the HLA antigens and CTLA4 gene polymorphisms in the overlapping has been suggested. The aim of this study was to investigate the alleles and genotypes frequency of the CTLA4 exon1 A49G polymorphism in Slovak patients with RA, Hashimoto thyroiditis (HT), both (RA + HT) and in healthy controls. Fifty-seven unrelated adults with RA, 57 patients with HT, 34 patients with both (RA + HT), and 51 normal subjects were studied. All were ethnic Slovaks living in the same geographical area. The CTLA4 exon1 A49G polymorphism was genotyped by using small amplicon melting analysis after real-time PCR. The CTLA4 49GG genotype and G allele frequency in the group with RA was not significantly higher in comparison with controls (10.53% vs. 9.8%, p = 0.62, OR 1.39, 95% CI 0.35–5.74 and 39.47% vs. 34.31%, p = 0.43, OR 1.25, 95% CI 0.72–2.18). The frequency of GG genotype was slightly but not significantly higher in patients with HT as compared with control group (19.3% vs. 9.8%, p = 0.17, OR 2.27, 95% CI 0.67–8.45). However, the frequency of GG genotype and G allele in patients with both RA and HT was significantly higher than that in controls (29.41% vs. 9.8%, p = 0.02, OR 4.49, 95% CI 1.20–18.54 and 51.47% vs. 34.31%, p = 0.03, OR 2.02, 95% CI 1.08–3.81). The frequency of GG genotype of CTLA4 A49G gene polymorphism in Slovak patients with RA is not significantly higher in comparison to control group. However, carriers of GG genotype with RA may be susceptible to develop HT.
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References
Gaches F, Delaire L, Nadalon S, Loustaud-Ratti V, Vidal E (1998) Frequency of autoimmune diseases in 218 patients with autoimmune thyroid pathologies. Rev Méd Interne 19:173–179
Biro E, Szekanecz Z, Czijak L, Danko K, Kiss E, Szabo NA, Szücz G, Zeher M, Bodolay E, Szegedi G, Bako G (2005) Association of systemic and thyroid autoimmune diseases. Clin Rheumatol 25:240–245
Masuko-Hongo K, Kato T (1999) The association between autoimmune thyroid disease and rheumatic disease: a review. Nippon Rinsho 57:1873–1877
Silman AJ, McGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE (1993) Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 32:903–907
Simmonds MJ, Howson JM, Heward JM, Carr-Smith J, Franklyn JA, Todd JA, Gough SC (2007) A novel and major association of HLA-C in Graves'disease that eclipses the classical HLA-DRB1 effect. Hum Mol Genet 16:2149–2153
Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678
Prahalad S, Hansen S, Whiting A, Guthery SL, Clifford B, McNally B, Zeft AS, Bohnsack JF, Jorde LB (2009) Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis. Arthritis Rheum 60:2124–2130
Hafler JP, Maier LM, Cooper JD et al (2009) CD226 Gly307Ser association with multiple autoimmune diseases. Gene Immun 10:5–10
Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA (1996) CTLA4: a negative regulator of autoimmune diseae. J Exp Med 184:783–788
Polymeropoulos MH, Xiao H, Rath DS, Merril CR (1991) Dinucleotide repeat polymorphism at the human CTLA4 gene. Nucleic Acids Res 19:4018–4019
Deichmann K, Heinzmann A, Brüggenolte E, Forster J, Kuehr J (1996) An Mse I RFLP in the human CTLA4 promotor. Biochem Biophys Res Commun 225:817–818
Larsen ZM, Kristiansen OP, Mato E, Johannesen J, Puig-Domingo M, de Leiva A, Nerup J, Pociot F (1999) IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1 diabetes (insulin-dependent). Autoimmunity 31:35–42
Kristiansen OP, Larsen ZM, Pociot F (2000) CTLA4 in autoimmune diseases - a general susceptibilty gene to autoimmunity? Gene Immun 1:170–184
Lee CS, Lee YJ, Liu HF, Su CH, Chang SC, Wang BR, Chen TL, Liu TL (2003) Association of CTLA4 gene A-G polymorphism with rheumatoid arthritis in Chinese. Clin Rheumatol 22:221–224
Vaidya B, Pearce SH, Charlton S, Marshall N, Rowan AD, Griffiths ID, Kendall-Taylor P, Cawston TE, Young-Min S (2002) An association between the CTLA4exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology 41:180–183
Seidl C, Donner H, Fisher B, Usadel KH, Seifried E, Kaltwasser JP, Badenhoop K (1998) CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis. Tissue Antigens 51:62–68
Yanagawa T, Gomi K, Nakao EI, Inada S (2000) CTLA4 gene polymorphism in Japanese patients with rheumatoid arthritis. J Rheumatol 27:2740–2742
Lei C, Dongqing Z, Yeqing S, Oaks MK, Lishan C, Jianzhong J, Jie Q, Fang D, Ningli L, Xinghai H, Daming R (2005) Association of the CTLA4 gene with rheumatoid arthritis in Chinese Han population. Eur J Hum Genet 13:823–828
Barton A, Myerscough A, John S, Gonzales-Gay M, Ollier W, Worthington J (2000) A single nucleotide polymorphism in exon 1 of cytotoxic T-lymphocyte- associated-4 (CTLA-4) is not associated with rheumatoid arthritis. Rheumatology 39:63–66
Matsushita M, Tsuchiya N, Oka T, Yamane A, Tokunaga K (2000) New polymorphisms of human CD80 and CD86: lack of association with rheumatoid arthritis and systemic lupus erythematosus. Gene Immun 1:428–434
Hadj Kacem H, Kaddour N, Adyel FZ, Bahloul Z, Ayadi H (2001) HLA-DQB1CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sjogren's syndrome. Rheumatology 40:1370–1374
Milicic A, Brown MA, Wordsworth BP (2001) Polymorhism in codon 17 of the CTLA4 gene (+49A/G) is not associated with susceptibility to rheumatoid arthritis in British Caucasians. Tissue Antigens 58:50–54
Lee YH, Choi SJ, Ji JD, Song GG (2002) No association of polymorhisms of the CTLA-4 exon 1 (+49) and promoter(−318) genes with rheumatoid arthritis in the Korean population. Scand J Rheumatol 31:266–270
Miterski B, Drynda S, Boschow G, Klein W, Oppermann J, Kekow J, Epplen JT (2004) Complex genetic predisposition in adult and juvenile rheumatoid arthritis. BMC Genet 5:2
Han S, Li Y, Mao Y, Xie Y (2005) Meta-analysis of the association of CTLA4 exon-1 +49A/G polymorphism with rheumatoid arthritis. Hum Genet 118:123–132
Tomer Y, Davies TF (2003) Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev 24:694–717
Heward JM, Allahabadia A, Armitage M, Hattersley A, Dodson PM, Macleod K, Carr-Smith J, Daykin J, Daly A, Sheppard MC, Holder RL, Barnett AH, Franklyn JA, Gough SC (1999) The development of Graves's disease and the CTLA4 gene on chromosome 2q33. J Clin Endocrinol Metab 84:2398–2401
Petrone A, Giorgi G, Mesturino CA, Capizzi M, Cascino I, Nistico L, Osborn J, Di Mario U, Buzzeti R (2001) Association of DRB1*04-DQB1*0301haplotype and lack of association of two polymorphic sites at CTLA4 gene with Hashimoto's thyroiditis in an Italian population. Thyroid 11:171–175
Zaletel K, Krhin B, Gaberscek S, Hojker S (2006) Thyroid autoantibody production is influenced by exon1 and promoter CTLA-4 polymorphisms in patients with Hashimoto's thyroiditis. Int J Immunogenet 33:87–91
Zaletel K, Krhin B, Gaberscek S, Pirnat E, Hojker S (2002) The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves'disease. Thyroid 12:373–376
Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, Xie Y, Mao Y (2006) CTLA4 polymorphisms and ophtalmopathy in Graves' disease patients: association study and meta-analysis. Hum Immunol 67:618–626
Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ (2000) 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
Maurer M, Loserth S, Kolb-Maurer A, Ponath A, Wiese S, Kruse N, Rieckmann P (2002) A polymorphism in the human cytotoxic T-lymphocyte antigen 4(CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1–8
Anjos S, Nguyen A, Ounissi-Benkalha H, Tessier MC, Polychronakos C (2002) A common autoimmunity predisposing signal peptide variant of the cytotoxic T- lymphocyte antigen 4 results in inefficient glycolysation of the susceptibility allele. J Biol Chem 277:46478–46486
Xu Y, Graves PN, Tomer Y, Davies TF (2002) CTLA-4 and autoimmune thyroid disease: lack of influence of the A49G signal peptide polymorphism on functional recombinant human CTLA-4. Cell Immunol 215:133–140
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Benhatchi, K., Jochmanová, I., Habalová, V. et al. CTLA4 exon1 A49G polymorphism in Slovak patients with rheumatoid arthritis and Hashimoto thyroiditis—results and the review of the literature. Clin Rheumatol 30, 1319–1324 (2011). https://doi.org/10.1007/s10067-011-1752-z
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DOI: https://doi.org/10.1007/s10067-011-1752-z