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.
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.


METHODS
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.
Kimura
Hironari
H
Department of Internal Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan.
Kato
Yoshiyuki
Y
Shimizu
Satoru
S
Takano
Kazue
K
Sato
Kanji
K
D000328:Adult; D000638:Amiodarone / Q000009:adverse effects*; D015703:Antigens, CD / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D006111:Graves Disease / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013959:Thyroid Diseases / Q000139:chemically induced*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000638:Amiodarone