细胞毒性T淋巴细胞相关因子4基因第1外显子49位多态性与难治性Graves病相关，但与胺碘酮相关性甲状腺功能障碍无关。

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.

作者信息

Kimura Hironari, Kato Yoshiyuki, Shimizu Satoru, Takano Kazue, Sato Kanji

机构信息

Department of Internal Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan.

出版信息

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

DOI:10.1089/thy.2009.0066

PMID:19731979

Abstract

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.

摘要

背景

最近，细胞毒性T淋巴细胞相关因子4（CTLA-4）外显子1单核苷酸多态性（CTLA-4 A/G(49)）的G等位基因已被确定为格雷夫斯病患者中最具信息量的标志物。G/G基因型的患者对药物治疗无效，停用抗甲状腺药物后经常复发。因此，我们分析了接受过碘-131（¹³¹I）治疗患者的CTLA-4 A/G(49)。此外，一份初步报告表明，胺碘酮相关性甲状腺功能障碍（AATD）与人类白细胞抗原（HLA）Ⅰ类和Ⅱ类有关。

方法

分析了415例日本格雷夫斯病患者和65例AATD患者外显子1（A/G(49)）和CT60的CTLA-4基因型。

结果

与正常受试者相比，格雷夫斯病患者中两种多态性的G等位基因和G/G基因型频率显著更高。与CT60相比，接受抗甲状腺药物治疗超过5年但促甲状腺素受体抗体仍持续阳性的患者中，A/G(49)的G等位基因和G/G基因型频率比促甲状腺素受体抗体在5年内转阴的患者更高（p < 0.0001）。因此，接受¹³¹I治疗的格雷夫斯病患者中，A/G(49)的G/G基因型和G等位基因频率也显著更高（p < 0.05）。然而，65例AATD患者的A/G多态性无显著差异。