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

Thyroid. 2009 Sep;19(9):975-81. doi: 10.1089/thy.2009.0066.


Background: Recently, the G allele of the cytotoxic T-lymphocyte-associated factor 4 (CTLA-4) exon 1 single-nucleotide polymorphism (CTLA-4 A/G(49)) 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/G(49) in patients who had been treated with (131)I. 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/G(49)) 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/G(49) 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/G(49) were also significantly higher in patients with Graves' disease who received (131)I 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/G(49)) is frequently expressed in Graves' disease patients who are refractory to antithyroid drug treatment. Therefore, the G/G genotype in A/G(49) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amiodarone / adverse effects*
  • Antigens, CD / genetics*
  • CTLA-4 Antigen
  • Female
  • Graves Disease / drug therapy
  • Graves Disease / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • T-Lymphocytes, Cytotoxic / immunology
  • Thyroid Diseases / chemically induced*


  • Antigens, CD
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Amiodarone