Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease
Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease
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DOI：
10.1093/hmg/ddp087
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Gough, Stephen C. L.
中科院分区：
文献类型：
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作者：
Brand, Oliver J.;Barrett, Jeffrey C.;Gough, Stephen C. L.
格雷夫斯病（GD）是一种常见的自身免疫性疾病（AID），它与其他艾滋病有许多相同的易感位点。促甲状腺激素受体（TSHR）代表GD的初级自身抗原，其中自身抗体与受体结合并模仿其配体促甲状腺激素，引起特征性临床表型。尽管早期调查TSHR和GD的研究证明是不确定的，但最近我们提供了令人信服的证据，证明TSHR区域与疾病有关。在目前的研究中，我们调查了98个snp的组合，包括70个标签snp，在扩展的800kb TSHR区域，以完善768名GD受试者和768名匹配对照的队列。共有28个SNP与GD相关（P < 0.05），其中相关性最强的位点为rs179247 (chi（2) = 32.45, P = 8.90 × 10(-8), OR = 1.53, 95% CI = 1.32 ~ 1.78）和rs12101255 (chi(2) = 30.91, P = 1.95 × 10(-7), OR = 1.55, 95% CI = 1.33 ~ 1.81)，均位于TSHR的内含子1。相关性最高的SNP rs179247在303个GD家族中被复制（P = 7.8 × 10(-4)）。此外，我们提供了初步证据，rs179247 （AA）和rs12101255 （TT）的疾病相关基因型显示，相对于两种替代的TSHR mRNA剪接变体，flTSHR的mRNA表达率降低。
Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 10(-7), OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 x 10(-4)). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.