Multiple SNPs in Intron 7 of Thyrotropin Receptor Are Associated with Graves’ Disease

Abstract

Our previous studies using microsatellite markers near or in the TSH receptor (TSHR) gene revealed significant association between autoimmune thyroid disease (AITD) in Japanese patients and TSHR microsatellite alleles. In the present study, we performed a case-control analysis of AITD using single-nucleotide polymorphisms (SNPs) spaced 3-50 kb apart spanning the TSHR gene. We observed significant associations between AITD/Graves' disease (GD)/Hashimoto's thyroiditis and multiple SNPs. Specifically, the SNP JST022302 and several adjacent SNPs in intron 7 of the TSHR gene were significantly associated with GD (P = 0.039-0.0004) but not Hashimoto's thyroiditis. Furthermore, we identified three haplotype blocks around intron 7 by linkage disequilibrium analysis. A single SNP haplotype [AATG(CT)6(TT)AG] in the haplotype block including JST022302 showed significant association with GD in haplotype case-control analysis (P = 0.0058). These findings suggest that alleles of intron 7 of the TSHR gene contribute to GD susceptibility.

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

“…A study from Singapore first demonstrated an association of a TSHR intron 1 SNP with GD (45). SNPs in intron 7 of the TSHR were also found to be associated with GD in the Japanese (46), and SNPs in intron 1 of the TSHR were reported to be associated with GD in Caucasians (47). We have recently confirmed this association of intron 1 with GD in Caucasians (48).…”

Influence of the TSH Receptor Gene on Susceptibility to Graves' Disease and Graves' Ophthalmopathy

“…Hence, much effort was focused on linkage and association studies with nearby microsatellite marker and exonic SNP analyses of the receptor over the past 12 years. Our original description of GD-1 (4) and its further delineation (7,13), about 10.8 Mb from the TSHR gene, has now been further refined using TSHR intronic SNPs (17,18,19). These data suggest that it may The numbers represent individual subjects or alleles, with the percentage in parentheses.…”

“…Recently, a study from Singapore demonstrated an association of a TSHR intron 1 SNP with GD (17). SNPs in intron 7 of the TSHR were also found to be associated with GD in Japanese (18), and SNPs in intron 1 of the TSHR were reported to be associated with GD in Caucasians (19).…”

Interleukin-12B Gene Polymorphism does not Confer Susceptibility to Graves' Ophthalmopathy in Japanese Population

“…The genetic susceptibility of these diseases is thought to be polygenic. It has been reported that major histocompatibility complex (MHC) gene [3,4], cytotoxic T lymphocyte antigen-4 (CTLA-4) gene [4][5][6], thyrotropin receptor (TSHR) gene [7], PTPN22 gene [8], CD40 gene [9,10], interferon-γ (IFN-γ) gene [11], tumor necrosis factor-α (TNF-α) gene [12,13] and interleukin-13 (IL-13) gene [14] polymorphisms are associated with GD and their interactions may influence disease phenotype and severity [3]. However, their contribution to susceptibility to GO awaits confirmation.…”