Association of Polymorphism at Position 49 in Exon 1 of the Cytotoxic T-Lymphocyte-Associated Factor 4 Gene with Graves' Disease Refractory to Medical Treatment,but Not with Amiodarone-Associated Thyroid Dysfunction

Abstract

Background:

Recently, the G allele of the cytotoxic T-lymphocyte-associated factor 4 (CTLA-4) exon 1 single-nucleotide polymorphism (CTLA-4 A/G⁴⁹) has been identified as the most informative marker in patients with Graves' disease. Patients with the G/G genotype are refractory to medical treatment and frequently relapse after discontinuation of antithyroid drugs. Therefore, we analyzed CTLA-4 A/G⁴⁹ in patients who had been treated with ¹³¹I. Further, a preliminary report has suggested that amiodarone-associated thyroid dysfunction (AATD) has a relationship with human leukocyte antigen (HLA) class I and class II.

Method:

CTLA-4 genotypes in exon 1 (A/G⁴⁹) and CT60 were analyzed in 415 Japanese patients with Graves' disease and 65 patients with AATD.

Results:

The frequencies of the G alleles and G/G genotype at the both polymorphisms were significantly higher in Graves' patients compared with normal subjects. Compared with CT60, the frequencies of the G alleles and G/G genotypes at the A/G⁴⁹ were more significantly higher in patients with persistently positive thyrotropin receptor antibody despite >5 years of antithyroid drug therapy, compared with those whose thyrotropin receptor antibody became negative in <5 years (p < 0.0001). Consequently, the frequencies of the G/G genotype and G allele at the A/G⁴⁹ were also significantly higher in patients with Graves' disease who received ¹³¹I therapy (p < 0.05). However, there was no significant difference in the A/G polymorphisms in the 65 patients with AATD.

Conclusions:

The G/G genotype in exon 1 (A/G⁴⁹) is frequently expressed in Graves' disease patients who are refractory to antithyroid drug treatment. Therefore, the G/G genotype in A/G⁴⁹ would be a useful predictor of Graves' patients who are suitable for radioiodine therapy. Although the number of analyzed patients was small, our preliminary data suggest that the CTLA-4 gene polymorphisms might be unassociated with AATD.