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01-01-2021 | Original Article

Polymorphisms of the genes CTLA4, PTPN22, CD40, and PPARG and their roles in Graves’ disease: susceptibility and clinical features

Authors: Natássia Elena Bufalo, Roberto Bernardo dos Santos, Angélica Gomes Rocha, Larissa Teodoro, João Hamilton Romaldini, Laura Sterian Ward

Published in: Endocrine | Issue 1/2021

Abstract

Purpose

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.

Methods

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).

Results

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).

Conclusions

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.

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.2008-0015CrossRefPubMedPubMedCentral

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.2009.02.007CrossRefPubMedPubMedCentral

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.86.2.7242CrossRefPubMed

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-xCrossRefPubMedPubMedCentral

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/nri1131CrossRefPubMed

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/nature01621CrossRefPubMed

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/39.1.63CrossRef

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.189.1.111CrossRefPubMedPubMedCentral

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.xCrossRefPubMedPubMedCentral

10.

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.2014.109CrossRefPubMedPubMedCentral

11.

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/ng1673CrossRefPubMed

12.

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)PubMed

13.

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/15.20.8125CrossRefPubMedPubMedCentral

14.

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.2010.213CrossRefPubMedPubMedCentral

15.

J. Auwerx, PPARgamma, the ultimate thrifty gene. Diabetologia 42, 1033–1049 (1999). https://doi.org/10.1007/s001250051268CrossRefPubMed

16.

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

17.

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/s00251-013-0702-0CrossRefPubMed

18.

M. Stumvoll, H. Häring, The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 51, 2341–2347 (2002). https://doi.org/10.2337/diabetes.51.8.2341CrossRefPubMed

19.

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/s40618-014-0228-9CrossRefPubMed

20.

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.2005.04.007CrossRefPubMed

21.

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/10.1159/000129676CrossRefPubMed

22.

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.28.42CrossRefPubMed

23.

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/s0004-27302013000300006CrossRef

24.

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.1003440CrossRefPubMedPubMedCentral

25.

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/btv195CrossRefPubMedPubMedCentral

26.

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.0046688CrossRefPubMedPubMedCentral

27.

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/gkj518CrossRefPubMedPubMedCentral

28.

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.2005.033878CrossRefPubMed

29.

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.20810CrossRefPubMed

30.

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/bth457CrossRefPubMed

31.

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.2013.56CrossRefPubMed

32.

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

33.

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

34.

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

35.

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

36.

W.M.Wiersinga, Thyroid autoimmunity. Endocr. Dev. (2014). https://doi.org/10.1159/000363161

37.

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

38.

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

39.

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

40.

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

41.

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

42.

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

43.

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

44.

L. Michelon, H. Vallada, Genética do transtorno bipolar. Brazilian J. Psychiatry 26, 12–16 (2004).CrossRef

Title: Polymorphisms of the genes CTLA4, PTPN22, CD40, and PPARG and their roles in Graves’ disease: susceptibility and clinical features
Authors: Natássia Elena Bufalo
Roberto Bernardo dos Santos
Angélica Gomes Rocha
Larissa Teodoro
João Hamilton Romaldini
Laura Sterian Ward
Publication date: 01-01-2021
Publisher: Springer US
Published in: Endocrine / Issue 1/2021
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-020-02337-x

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Polymorphisms of the genes CTLA4, PTPN22, CD40, and PPARG and their roles in Graves’ disease: susceptibility and clinical features

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

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