Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves' ophthalmopathy in European and Japanese populations

Abstract

Objective: The development and severity of Graves' ophthalmopathy (GO) may result from a complex interplay of genetic and environmental factors. The aim of this study was to investigate the association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors (age, sex, cigarette smoking) with GO in two different populations, Polish-Caucasians and Japanese. Design: We investigated the distribution of CTLA-4 A49G polymorphism in 264 Caucasian patients with Graves' disease (GD), of which 95 had clinically evident GO (NOSPECS class $ 3) and 319 Japanese patients with GD, of which 99 had ophthalmopathy. The control groups consisted of healthy Polish adults ðn ¼ 194Þ; Polish centenarians ðn ¼ 51Þ and Japanese adults ðn ¼ 112Þ: Results: Allele G and G/G genotype were significantly increased in Caucasian patients with GD (48% and 25% respectively) and in Japanese patients with GD (69% and 47% respectively) compared with control groups. There were no significant differences in the G allele and G/G genotype frequencies in GO patients compared with GD patients without ophthalmopathy. Multiple logistic regression analysis demonstrated that cigarette smoking ðP ¼ 0:03; odds ratio ðORÞ ¼ 1:7Þ and age of onset of GD over 42 years ðP ¼ 0:08; OR ¼ 1:6Þ were contributing factors associated with susceptibility to GO in Polish patients. In Japanese patients, a younger age of onset of GD had an effect on the development of GO ðP ¼ 0:02; OR ¼ 1:8Þ: Conclusions: (i) Allele G and G/G genotype confer genetic susceptibility to GD; (ii) CTLA-4 A49G polymorphism is not associated with the development of GO; (iii) different non-genetic factors may contribute to GO in different populations.

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

“…29 Apart from NFKB1 genotypes, no other variables had a significant effect on the development of ophthalmopathy in Japanese GD patients, confirming our previous results. 30 Thus, the predisposing factors to ophthalmopathy in Japanese population remain to be established.…”

A Study on the Level of T3, T4, TSH and the Association of A/G Polymorphism with CTLA-4 Gene in Graves’ Hyperthyroidism among South Indian Population

“…The susceptibility genes are human leucocyte antigen (HLA), GD-1, GD-2 and GD-3 [4] and cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) [5][6][7]. It has been suggested that the CTLA-4 gene polymorphism plays an important role in the development of Graves' hyperthyroidism in various populations [8,9].…”

Interleukin-12B Gene Polymorphism does not Confer Susceptibility to Graves' Ophthalmopathy in Japanese Population

“…The genetic susceptibility of these diseases is thought to be polygenic. It has been reported that major histocompatibility complex (MHC) gene [3,4], cytotoxic T lymphocyte antigen-4 (CTLA-4) gene [4][5][6], thyrotropin receptor (TSHR) gene [7], PTPN22 gene [8], CD40 gene [9,10], interferon-γ (IFN-γ) gene [11], tumor necrosis factor-α (TNF-α) gene [12,13] and interleukin-13 (IL-13) gene [14] polymorphisms are associated with GD and their interactions may influence disease phenotype and severity [3]. However, their contribution to susceptibility to GO awaits confirmation.…”