CTLA4, PTPN22, and CD40 are immune-regulatory genes strongly associated with GD, as well as PPARG, but their clinical significance in different populations is still uncertain.
We genotyped 282 Brazilian GD patients (234 women and 48 men, 39.80 ± 11.69 years old), including 144 patients with GO, and 308 healthy control individuals (246 women and 62 men, 36.86 ± 12.95 years old).
A multivariate analysis demonstrated that the inheritance of the GG genotype rs3087243 of CTLA4 (OR = 2.593; 95% CI = 1.630–4.123; p < 0.0001) and the CC genotype of rs3789607 of PTPN22 (OR = 2.668; 95% CI = 1.399–5.086; p = 0.0029) consisted in factors independent of the susceptibility to GD. The inheritance of polymorphic genotypes of rs5742909 of CTLA4 was associated with older age at the time of diagnosis (42.90 ± 10.83 versus 38.84 ± 11.81 years old; p = 0.0105), with higher TRAb levels (148.17 ± 188.90 U/L versus 112.14 ± 208.54 U/L; p = 0.0229) and the need for higher therapeutic doses of radioiodine (64.23 ± 17.16 versus 50.22 ± 16.86; p = 0.0237). The inheritance of the CC genotype of rs1883832 CD40 gene was more frequent among women (69.65%) than men (52.00%; p = 0.0186). The polymorphic genotype of PPARG gene (rs1801282) was associated with TPOAb positivity (p = 0.0391), and the GG genotype of rs2476601 of PTPN22 gene was associated with positivity for both TgAb (p = 0.0360) and TPOAb (p < 0.0001). Both polymorphic genotypes rs2476601 and rs3789607 of the PTPN22 gene were more frequent among nonsmoking patients (p = 0.0102 and p = 0.0124, respectively).
Our data confirm the important role of CTLA4 polymorphisms in GD susceptibility; demonstrate the role of PTPN22 polymorphisms in patients’ clinical features; and suggest these genes may influence the severity of the disease.
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A. Huber, F. Menconi, S. Corathers, E.M. Jacobson, Y. Tomer, Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr. Rev. 29, 697–725 (2008). https://doi.org/10.1210/er.2008-0015
Y. Tomer, A. Huber, The etiology of autoimmune thyroid disease: a story of genes and environment. J. Autoimmun. 32, 231–239 (2009). https://doi.org/10.1016/j.jaut.2009.02.007
T.H. Brix, K.O. Kyvik, K. Christensen, L. Hegedüs, 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). https://doi.org/10.1210/jcem.86.2.7242
A. Hasham, Y. Tomer, Genetic and epigenetic mechanisms in thyroid autoimmunity. Immunol. Res. 54, 204–213 (2012). https://doi.org/10.1007/s12026-012-8302-x
C.E. Rudd, H. Schneider, Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat. Rev. Immunol. 3, 544–556 (2003). https://doi.org/10.1038/nri1131
H. Ueda, J.M. Howson, L. Esposito, J. Heward, H. Snook, G. Chamberlain, D.B. Rainbow, K.M. Hunter, A.N. Smith, G. Di Genova, M.H. Herr, I. Dahlman, F. Payne, D. Smyth, C. Lowe, R.C. Twells, S. Howlett, B. Healy, S. Nutland, H.E. Rance, V. Everett, L.J. Smink, A.C. Lam, H.J. Cordell, N.M. Walker, C. Bordin, J. Hulme, C. Motzo, F. Cucca, J.F. Hess, M.L. Metzker, J. Rogers, S. Gregory, A. Allahabadia, R. Nithiyananthan, E. Tuomilehto-Wolf, J. Tuomilehto, P. Bingley, K.M. Gillespie, D.E. Undlien, K.S. Rønningen, C. Guja, C. Ionescu-Tîrgovişte, D.A. Savage, A.P. Maxwell, D.J. Carson, C.C. Patterson, J.A. Franklyn, D.G. Clayton, L.B. Peterson, L.S. Wicker, J.A. Todd, S.C. Gough, Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003). https://doi.org/10.1038/nature01621
A. Barton, A. Myerscough, S. John, M. Gonzalez-Gay, W. Ollier, J. Worthington, A single nucleotide polymorphism in exon 1 of cytotoxic T-lymphocyte-associated-4 (CTLA-4) is not associated with rheumatoid arthritis. Rheumatol 39, 63–66 (2000). https://doi.org/10.1093/rheumatology/39.1.63
J.F. Cloutier, A. Veillette, Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med. 189, 111–121 (1999). https://doi.org/10.1084/jem.189.1.111
R.L. Smith, R.B. Warren, S. Eyre, X. Ke, H.S. Young, M. Allen, D. Strachan, W. McArdle, M.P. Gittins, J.N. Barker, C.E. Griffiths, J. Worthington, Polymorphisms in the PTPN22 region are associated with psoriasis of early onset. Br. J. Dermatol. 158, 962–968 (2008). https://doi.org/10.1111/j.1365-2133.2008.08482.x
S.M. Stanford, N. Bottini, PTPN22: the archetypal non-HLA autoimmunity gene. Nat. Rev. Rheumatol. 10, 602–611 (2014). https://doi.org/10.1038/nrrheum.2014.109
T. Vang, M. Congia, M.D. Macis, L. Musumeci, V. Orrú, P. Zavattari, K. Nika, L. Tautz, K. Taskén, F. Cucca, T. Mustelin, N. Bottini, Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37, 1317–1319 (2005). https://doi.org/10.1038/ng1673
R.J. Armitage, B.M. Macduff, M.K. Spriggs, W.C. Fanslow, Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines. J. Immunol. 150, 3671–3680 (1993)
M. Kozak, An analysis of 5’-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987). https://doi.org/10.1093/nar/15.20.8125
M.V. Schmidt, B. Brüne, A. von Knethen, The nuclear hormone receptor PPARγ as a therapeutic target in major diseases. ScientificWorldJournal 10, 2181–2197 (2010). https://doi.org/10.1100/tsw.2010.213
J. Auwerx, PPARgamma, the ultimate thrifty gene. Diabetologia 42, 1033–1049 (1999). https://doi.org/10.1007/s001250051268
A. Antonelli, S.M. Ferrari, S. Frascerra, I. Ruffilli, C. Pupilli, G. Bernini, S. Sellari-Franceschini, S. Gelmini, E. Ferrannini, P. Fallahi, CCL2 and α (CXCL10) chemokine modulations by cytokines and peroxisome proliferator-activated receptor-α agonists in Graves’ ophthalmopathy. J. Endocrinol. 213, 183–191 (2012). https://doi.org/10.1530/JOE-11-0488
E. Pawlak-Adamska, J. Daroszewski, M. Bolanowski, J. Oficjalska, P. Janusz, M. Szalinski, I. Frydecka, PPARg2 Ala12 variant protects against Graves’ orbitopathy and modulates the course of the disease. Immunogenetics 65, 493–500 (2013). https://doi.org/10.1007/s00251-013-0702-0
M. Stumvoll, H. Häring, The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 51, 2341–2347 (2002). https://doi.org/10.2337/diabetes.51.8.2341
N.E. Bufalo, R.B. Dos Santos, M.A. Marcello, R.P. Piai, R. Secolin, J.H. Romaldini, L.S. Ward, TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves’ disease and Graves’ ophthalmopathy. J. Endocrinol. Invest 38, 555–561 (2015). https://doi.org/10.1007/s40618-014-0228-9
V.B. Guzman, A. Morgun, N. Shulzhenko, K.L. Mine, A. Gonçalves-Primo, C.C. Musatti, M. Gerbase-Delima, Characterization of CD28, CTLA4, and ICOS polymorphisms in three Brazilian ethnic groups. Hum. Immunol. 66, 773–776 (2005). https://doi.org/10.1016/j.humimm.2005.04.007
A. Namo Cury, C.A. Longui, C. Kochi, L.E. Calliari, N. Scalissi, J.E. Salles, M. Neves Rocha, Barbosa de Melo, M., Rezende Melo, M., Monte, O.: Graves’ disease in Brazilian children and adults: lack of genetic association with CTLA-4 +49A>G polymorphism. Horm. Res. 70, 36–41 (2008). https://doi.org/10.1159/000129676
N.A. Tavares, M.M. Santos, R. Moura, J. Araújo, R.L. Guimarães, S. Crovella, L.A. Brandão, Association of TNF-α, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil. Genet Mol. Res. 14, 18936–18944 (2015). https://doi.org/10.4238/2015.December.28.42
A.L. Maia, R.S. Scheffel, E.L. Meyer, G.M. Mazeto, G.A. Carvalho, H. Graf, M. Vaisman, L.M. Maciel, H.E. Ramos, A.J. Tincani, N.C. Andrada, L.S. Ward, B.S. Metabolism, of E. and: The Brazilian consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq. Bras. Endocrinol. Metab. 57, 205–232 (2013). https://doi.org/10.1590/s0004-27302013000300006
J. Bendl, J. Stourac, O. Salanda, A. Pavelka, E.D. Wieben, J. Zendulka, J. Brezovsky, J. Damborsky, PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol. 10, e1003440 (2014). https://doi.org/10.1371/journal.pcbi.1003440
Y. Choi, A.P. Chan, PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16), 2745–2747 (2015). https://doi.org/10.1093/bioinformatics/btv195
Y. Choi, G.E. Sims, S. Murphy, J.R. Miller, A.P. Chan, Predicting the functional effect of amino acid substitutions and indels. PLoS ONE 7, e46688 (2012). https://doi.org/10.1371/journal.pone.0046688
E. Mathe, M. Olivier, S. Kato, C. Ishioka, P. Hainaut, S. Tavtigian, V: Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res. 34, 1317–1325 (2006). https://doi.org/10.1093/nar/gkj518
S.V. Tavtigian, A.M. Deffenbaugh, L. Yin, T. Judkins, T. Scholl, P.B. Samollow, D. de Silva, A. Zharkikh, A. Thomas, Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J. Med. Genet. 43, 295–305 (2006). https://doi.org/10.1136/jmg.2005.033878
J. Cheng, A. Randall, P. Baldi, Prediction of protein stability changes for single-site mutations using support vector machines. Proteins 62, 1125–1132 (2006). https://doi.org/10.1002/prot.20810
J.C. Barrett, B. Fry, J. Maller, M.J. Daly, Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005). https://doi.org/10.1093/bioinformatics/bth457
M.J. Simmonds, GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis. Nat. Rev. Endocrinol. 9, 277–287 (2013). https://doi.org/10.1038/nrendo.2013.56
J. Ni, L. J. Qiu, M. Zhang, P. F. Wen, X. R. Ye, Y. Liang, H. F. Pan, D. Q. Ye, CTLA-4 CT60 (rs3087243) polymorphism and autoimmune thyroid diseases susceptibility: a comprehensive meta-analysis. Endocr. Res. (2014). https://doi.org/10.3109/07435800.2013.879167
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 (2013). https://doi.org/10.1371/journal.pone.0059349
E. Pawlak-Adamska, I. Frydecka, M. Bolanowski, A. Tomkiewicz, A. Jonkisz, L. Karabon, A. Partyka, O. Nowak, M. Szalinski, J. Daroszewski, CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves’ disease and modulates clinical phenotype of disease. Endocrine (2017). https://doi.org/10.1007/s12020-016-1096-1
X. B. Wang, X. Zhao, R. Giscombe, A.K. Lefvert, A CTLA-4 gene polymorphism at position -318 in the promoter region affects the expression of protein. Genes Immun. (2002). https://doi.org/10.1038/sj.gene.6363869
W.M.Wiersinga, Thyroid autoimmunity. Endocr. Dev. (2014). https://doi.org/10.1159/000363161
M. Ichimura, H. Kaku, T. Fukutani, H. Koga, T. Mukai, I. Miyake, K. Yamada, Y. Koda, Y. Hiromatsu, Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves’ disease in a Japanese population. Thyroid (2008). https://doi.org/10.1089/thy.2007.0353
S. Tang, W. Peng, C. Wang, H. Tang, Q. Zhang, Association of the PTPN22 gene (+1858C/T, −1123G/C) polymorphisms with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res. Clin. Pract. (2012). https://doi.org/10.1016/j.diabres.2012.04.011
T.F. Davies, R. Latif, X. Yin, New genetic insights from autoimmune thyroid disease. J. Thyroid Res. (2012). https://doi.org/10.1155/2012/623852
T.C. Dakal, D. Kala, G. Dhiman, V. Yadav, A. Krokhotin, N.V. Dokholyan, Predicting the functional consequences of non-synonymous single nucleotide polymorphisms in IL8 gene. Sci. Rep. (2017). https://doi.org/10.1038/s41598-017-06575-4
X. Wang, D.J. Tomso, X. Liu, D.A. Bell, Single nucleotide polymorphism in transcriptional regulatory regions and expression of environmentally responsive genes. Toxicol. Appl. Pharmacol. (2005). https://doi.org/10.1016/j.taap.2004.09.024
J. Liu, J. Fu, Y. Duan, G. Wang, Predictive value of gene polymorphisms on recurrence after the withdrawal of antithyroid drugs in patients with Graves’ disease. (2017) https://doi.org/10.3389/fendo.2017.00258
Y. Tu, G. Fan, Y. Dai, T. Zeng, F. Xiao, L. Chen, W. Kong, Association between rs3087243 and rs231775 polymorphism within the cytotoxic T-lymphocyte antigen 4 gene and Graves’ disease: a case/control study combined with meta-analyses. Oncotarget. (2017). https://doi.org/10.18632/oncotarget.22702
L. Michelon, H. Vallada, Genética do transtorno bipolar. Brazilian J. Psychiatry 26, 12–16 (2004).
The authors thank the statisticians of the School of Medical Sciences of UNICAMP. A special thanks to the group of the Laboratory of Cancer Molecular Genetics (GEMOCA) of the School of Medical Sciences. This study received financial support, grant #200806567–5, from the São Paulo Research Foundation (FAPESP). The authors would like to thank Espaço da Escrita—Pró-Reitoria de Pesquisa—UNICAMP—for the language services provided.
This study received financial support, grant #2008/06567–5, from the São Paulo Research Foundation (FAPESP).
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The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Research Ethics Committee of the School of Medical Sciences—University of Campinas (FCM—UNICAMP) (#6212008) and the Pontifical Catholic University of Campinas (PUCCAMP) (#33204), Brazil and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Bufalo, N.E., dos Santos, R.B., Rocha, A.G. et al. Polymorphisms of the genes CTLA4, PTPN22, CD40, and PPARG and their roles in Graves’ disease: susceptibility and clinical features. Endocrine 71, 104–112 (2021). https://doi.org/10.1007/s12020-020-02337-x
- Graves’ Disease