Cytotoxic T lymphocyte-associated molecule-4 polymorphisms in Turkish Graves' disease patients and association with probability of remission after antithyroid therapy.

ABSTRACT

BACKGROUND: One of the candidate genes for susceptibility to Graves' disease (GD) is cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a negative regulator of T-cell activation. In order to elucidate the relationship of GD with the A/G polymorphism in exon 1 and the C/T polymorphism in the promoter region of the CTLA-4 gene, the frequency of these two polymorphisms was identified in 98 healthy individuals and 77 patients with GD. METHODS: Polymorphisms were analyzed using a PCR-RFLP method. We also examined the relationship between the A/G polymorphism and various clinical and laboratory variables among patients with GD. All patients were treated with an initial dose of propranolol (40-60 mg /day) and PTU (300-400 mg/day). Subjects remained on this treatment for a minimum of 6 months and were followed in our clinic for 1 year after cessation of treatment. RESULTS: The frequency of the GG genotype was significantly higher among patients with GD than among controls of both sexes (P<0.05; odds ratio=3.145, 95% CI=1.212-8.161). There was no difference between patients and controls with regard to the C/T polymorphism. There was no statistical difference in age, sex, cigarette smoking, initial serum thyroid hormone levels, initial goiter size, initial TSH-receptor antibodies, or NOSPECS classification for orbitopathy among the patients with the three different genotypes (GG, AG, and AA). Of the patients with the AA genotype, 17 of 29 (58.6%) were in remission 1 year after PTU withdrawal, while 18 of 33 patients (54.4%) with the AG genotype were in remission 1 year later. However, only 3 of 15 patients (20%) with the GG genotype were in remission 1 year after withdrawal of antithyroid drug therapy (P=0.016 GG/AA, P=0.025 GG/AG). Using 1 year after discontinuation of antithyroid drug therapy as the cut-off point for multivariate logistic regression analysis, we found that the GG genotype, TSH at the end of therapy, and age were independent risk factors for recurrence. CONCLUSION: We conclude that the occurrence of GD is linked to the A/G polymorphism of the CTLA molecule in the Turkish population and is associated with a lower chance of remission after discontinuation of PTU treatment.