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


CONCLUSIONS
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.
Sahin
Mustafa
M
Department of Endocrinology and Metabolic Diseases Department, Ankara University School of Medicine, Ibni Sina Hospital, Ankara, Turkey.
Erdogan
Murat Faik
MF
Erdogan
Gurbuz
G