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 (n = 194), Polish centenarians (n = 51) and Japanese adults (n = 112). 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 (P = 0.03, odds ratio (OR) = 1.7) and age of onset of GD over 42 years (P = 0.08; OR = 1.6) 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 (P = 0.02, OR = 1.8). 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.