细胞毒性T淋巴细胞相关蛋白4（CTLA-4）基因、促甲状腺激素受体（TSHR）基因及调节性T细胞作为格雷夫斯病患者复发风险因素的作用

The Role of Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) Gene, Thyroid Stimulating Hormone Receptor (TSHR) Gene and Regulatory T-cells as Risk Factors for Relapse in Patients with Graves Disease.

作者信息

Eliana Fatimah, Suwondo Pradana, Asmarinah Asmarinah, Harahap Alida, Djauzi Samsuridjal, Prihartono Joedo, Pemayun Tjokorda Gde Dalem

机构信息

Department of Internal Medicine, Faculty of Medicine, YARSI University, Jakarta, Indonesia.

出版信息

Acta Med Indones. 2017 Jul;49(3):195-204.

PMID:29093229

Abstract

BACKGROUND

graves' disease (GD) is the most common condition of thyrotoxicosis. The management of GD is initiated with the administration of antithyroid drugs; however, it requires a long time to achieve remission. In reality more than 50% of patients who had remission may be at risk for relapse after the drug is stopped. This study aimed to evaluate the role of clinical factors such as smoking habit, degree of ophtalmopathy, degree of thyroid enlargement; genetic factors such as CTLA-4 gene on nucleotide 49 at codon 17 of exon 1, CTLA-4 gene of promotor -318, TSHR gene polymorphism rs2268458 of intron 1; and immunological factors such as regulatory T cells (Treg) and thyroid receptor antibody (TRAb); that affecting the relapse of patients with Graves' disease in Indonesia.

METHODS

this was a case-control study, that compared 72 subjects who had relapse and 72 subjects without relapse at 12 months after cessation of antithyroid treatment, who met the inclusion criteria. Genetic polymorphism examination was performed using PCR-RFLP. The number of regulatory T cells was counted using flow cytometry analysis and ELISA was used to measure TRAb. The logistic regression was used since the dependent variables were categorical variables.

RESULTS

the analysis of this study demonstrated that there was a correlation between relapse of disease and family factors (p=0.008), age at diagnosis (p=0.021), 2nd degree of Graves' ophthalmopathy (p=0.001), enlarged thyroid gland, which exceeded the lateral edge of the sternocleidomastoid muscles (p=0.040), duration of remission period (p=0.029), GG genotype of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1 (p=0.016), CC genotype of TSHR gene on the rs2268458 of intron 1 (p=0.003), the number of regulatory T cells (p=0.001) and TRAb levels (p=0.002).

CONCLUSION

genetic polymorphisms of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1, TSHR gene SNP rs2268458 of intron 1, number of regulatory T cells and TRAb levels play a role as risk factors for relapse in patients with Graves' disease.

摘要

背景

格雷夫斯病（GD）是甲状腺毒症最常见的病症。GD的治疗始于抗甲状腺药物的给药；然而，实现缓解需要很长时间。实际上，超过50%实现缓解的患者在停药后可能有复发风险。本研究旨在评估诸如吸烟习惯、眼病程度、甲状腺肿大程度等临床因素；诸如第1外显子第17密码子核苷酸49处的CTLA-4基因、启动子-318的CTLA-4基因、内含子1的TSHR基因多态性rs2268458等遗传因素；以及诸如调节性T细胞（Treg）和甲状腺受体抗体（TRAb）等免疫因素；对印度尼西亚格雷夫斯病患者复发的影响。

方法

这是一项病例对照研究，比较了72例复发患者和72例在抗甲状腺治疗停止12个月后未复发且符合纳入标准的患者。使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）进行基因多态性检测。使用流式细胞术分析计数调节性T细胞数量，并使用酶联免疫吸附测定（ELISA）测量TRAb。由于因变量是分类变量，因此使用逻辑回归分析。

结果

本研究分析表明，疾病复发与家族因素（p=0.008）、诊断时年龄（p=0.021）、格雷夫斯眼病二级（p=0.001）、甲状腺肿大超过胸锁乳突肌外侧边缘（p=0.040）、缓解期持续时间（p=0.029）、第1外显子第17密码子核苷酸49处CTLA-4基因的GG基因型（p=0.016）、内含子1的rs2268458处TSHR基因的CC基因型（p=0.003）、调节性T细胞数量（p=0.001）和TRAb水平（p=0.002）之间存在相关性。