Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
PLoS One. 2012;7(5):e37501. doi: 10.1371/journal.pone.0037501. Epub 2012 May 25.
The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD) and Hashimoto's thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Two whole genome scans from Japan and from the US identified a locus on chromosome 8q24 that showed evidence for linkage with AITD and HT. Recent studies have demonstrated an association between thyroglobulin (Tg) polymorphisms and AITD in Caucasians, suggesting that Tg is a susceptibility gene on 8q24.
The objective of the study was to refine Tg association with AITD, by analyzing a panel of 25 SNPs across an extended 260 kb region of the Tg.
We studied 458 Japanese AITD patients (287 GD and 171 HT patients) and 221 matched Japanese control subjects in association studies. Case-control association studies were performed using 25 Tg single nucleotide polymorphisms (SNPs) chosen from a database of the Single Nucleotide Polymorphism Database (dbSNP). Haplotype analysis was undertaken using the computer program SNPAlyze version 7.0.
In total, 5 SNPs revealed association with GD (P<0.05), with the strongest SNP associations at rs2256366 (P = 0.002) and rs2687836 (P = 0.0077), both located in intron 41 of the Tg gene. Because of the strong LD between these two strongest associated variants, we performed the haplotype analysis, and identified a major protective haplotype for GD (P = 0.001). These results suggested that the Tg gene is involved in susceptibility for GD and AITD in the Japanese.
自身免疫性甲状腺疾病（AITD），包括格雷夫斯病（GD）和桥本甲状腺炎（HT）的病因很大程度上是未知的。然而，遗传易感性被认为起主要作用。来自日本和美国的两项全基因组扫描在染色体 8q24 上发现了一个与 AITD 和 HT 有连锁证据的位点。最近的研究表明，甲状腺球蛋白（Tg）多态性与高加索人群的 AITD 之间存在关联，提示 Tg 是 8q24 上的一个易感基因。
本研究通过分析 Tg 延长 260kb 区域内的 25 个 SNP 来进一步确定 Tg 与 AITD 的关联。
我们在关联研究中研究了 458 名日本 AITD 患者（287 名 GD 和 171 名 HT 患者）和 221 名匹配的日本对照。使用从单核苷酸多态性数据库（dbSNP）数据库中选择的 25 个 Tg 单核苷酸多态性（SNP）进行病例对照关联研究。使用计算机程序 SNPAlyze 版本 7.0 进行单体型分析。
共有 5 个 SNP 与 GD 存在关联（P<0.05），其中最强的 SNP 关联位于 Tg 基因 41 号内含子的 rs2256366（P=0.002）和 rs2687836（P=0.0077）。由于这两个最强相关变体之间存在强烈的 LD，我们进行了单体型分析，确定了 GD 的主要保护单体型（P=0.001）。这些结果表明 Tg 基因参与了日本人群 GD 和 AITD 的易感性。
