Yin Xiaoming, Latif Rauf, Bahn Rebecca, Tomer Yaron, Davies Terry F
Thyroid Research Unit, Mount Sinai School of Medicine, James J. Peters VA Medical Center, New York, New York, USA.
Thyroid. 2008 Nov;18(11):1201-6. doi: 10.1089/thy.2008.0098.
A large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.
We used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians).
The allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP.
These results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
本实验室首次描述了一个名为GD - 1的大基因区域，其与格雷夫斯病（GD）相关，且包含促甲状腺激素受体（TSHR）基因。最近的研究表明TSHR内含子多态性与GD有关。我们借此机会对一群特征明确的自身免疫性甲状腺疾病（AITD）患者进行研究，这些患者还针对另一个甲状腺易感基因——细胞毒性T淋巴细胞抗原4（CTLA - 4）的免疫调节基因进行了分型，以研究其与TSHR基因多态性赋予的GD易感性之间的关系。
我们使用位于TSHR基因第1内含子的TSHR - SNP - rs2268458，通过标准的PCR - RFLP程序进行检测，作为TSHR基因关联的标志物。我们对200例GD患者、83例桥本甲状腺炎（HT）患者和118名健康对照者（均为白种女性）进行了基因分型。
GD患者的等位基因和基因型频率与对照组有显著差异，但HT患者与对照组无显著差异。GD患者中联合基因型（等位基因）CC + TC的频率显著高于对照组，提示含C的基因型以显性方式增加了GD的发病风险（p = 0.018，比值比[OR] = 1.8）。与CTLA - 4（A/G）(49)单核苷酸多态性（SNP）相比，我们未能在已确诊的AITD患者中证明存在累加风险。此外，将患者（n = 120）分为有临床显著意义的格雷夫斯眼病（GO）患者亚组，结果显示与TSHR SNP无关联。
这些结果表明，TSHR内含子SNP - rs2268458与GD相关，但与HT无关，这表明TSHR基因有可能增加GD的易感性。然而，我们未能证明与CTLA - 4（A/G）(49) SNP存在任何累加风险，因此，它是AITD的一个独立危险因素。这表明，在研究人群的范围内，这两个基因各自对GD易感性的贡献较小，且都不是必需的。此外，没有证据表明TSHR基因关联会增加发生GO的风险。现在需要进行直接的功能分析，以帮助解释TSHR基因对GD易感性的机制。
