Kimura Hironari, Kato Yoshiyuki, Shimizu Satoru, Takano Kazue, Sato Kanji
Department of Internal Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan.
Thyroid. 2009 Sep;19(9):975-81. doi: 10.1089/thy.2009.0066.
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.
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.
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.
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.
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。
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。
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。
外显子1（A/G(49)）的G/G基因型在对抗甲状腺药物治疗无效的格雷夫斯病患者中频繁出现。因此，A/G(49)的G/G基因型将是适合放射性碘治疗的格雷夫斯病患者的有用预测指标。虽然分析的患者数量较少，但我们的初步数据表明CTLA-4基因多态性可能与AATD无关。
