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



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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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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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

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  • Graves’ Disease
  • Polymorphism
  • CTLA4
  • PTPN22
  • CD40