Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

Abstract

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.

Association between thyroid stimulating hormone receptor gene intron polymorphisms and autoimmune thyroid disease in a Chinese Han population

“…Our study for single SNPs had 80% power (α=0.05) to detect a significant difference between ing the chances of autoantibody production against the TSHR. It has been reported that rs179247 and rs12101255 increase the level of ST4 and ST5 expressions compared to full length TSHR, and may support the hypothesis for disease pathogenesis [13]. In summary, we can conclude that the SNPs in TSHR intron1 and 8 are significantly associated with pathogenesis of AITD.…”

“…The case-control study in Japanese cohorts found that several SNPs spaced 3-50kb apart spanning the TSHR gene in intron7 and 8 were associated with GD, especially rs2268475(P=0.0004), rs1990595 (P=0.0086) and rs3783938 (P=0.0099) [12]. More recently, a screening for 98 SNPs spanning about 800kb of TSHR gene in UK European ancestry found that 28 SNPs were associated with GD, in which the most relevant SNPs were rs179247 (P=8.9×10 -8 , OR=1.53) and rs12101255 (P=1.95×10 -7 , OR=1.55) [13]. They also selected several SNPs from intron7, but no association was observed.…”

“…Currently, several candidate genes have been reported, which include human leukocyte antigen (HLA) [4][5][6], cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) [7][8][9], thyroid stimulating hormone receptor (TSHR) [10][11][12][13][14], thyroglobulin (TG) [15,16], protein tyrosine phosphatase (PTPN) gene [17,18], CD40 gene [19,20] and FCRL3 gene [21]. Among these genes, TSHR is deemed to be an important autoantigen for thyroid and definitely plays a significant role in the pathogenesis of AITD [22].…”

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

“…3,4 In the smaller of the two studies, the WTCCC investigated 5500 individuals, which included 900 cases with GD, using a genome-wide set of 14 500 nonsynonymous coding single-nucleotide polymorphisms (nsSNPs). Although the strongest association signal was unsurprisingly identified in the human leukocyte antigen (HLA) region (P valueo10 À20 ), association was also confirmed at the previously reported thyroid stimulating hormone receptor gene (TSHR) 5 and Fc receptor-like 3 gene (FCRL3), 4,6 with a further nine novel regions showing some evidence of association with P valuep10 À4 . 4 The aim of this study was to try to replicate the association identified in the nine novel regions in an independent UK collection of GD subjects and controls.…”

“…The FCRL and TSHR regions were not examined as association with AITD had been previously reported. [4][5][6] A further tenth SNP, rs3748140, present within the protein phosphatase 1 regulatory inhibitor Subunit 3B gene (PPPIR38) also produced a point-wise significance level of Pp10 À4 but was excluded from further analysis as it was non-polymorphic in the replication study.…”