TSHR Gene Polymorphisms in the Enhancer Regions Are Most Strongly Associated with the Development of Graves' Disease, Especially Intractable Disease, and of Hashimoto's Disease

Background: Graves' disease (GD) and Hashimoto's disease (HD) are autoimmune thyroid disorders distinguished by the presence or absence of antithyrotropin receptor (TSHR) antibodies (TRAb). TSHR gene polymorphisms determine the amount of TSHR expressed, which may in turn influence TRAb production. The FANTOM5 project identified six GD-associated single nucleotide polymorphisms (SNPs) within the enhancer regions of the TSHR and unknown genes. This study examined the association of 11 TSHR and unknown gene polymorphisms, five of which are located in TSHR enhancer regions, with the development and prognosis of GD and HD. Methods: SNPs of the TSHR and unknown genes were genotyped in 180 GD patients, including 62 patients with intractable GD and 48 patients with GD in remission; 151 HD patients, including 65 patients with severe HD and 40 patients with mild HD; and 111 healthy controls. Results: The rs4411444 GG genotype and G allele, the rs2300519 AA genotype, and the rs179247 AA genotype and A allele were more frequent in GD patients than they were in controls. These same genotypes and alleles, in addition to the rs2300519A allele and rs4903961 GG genotype and G allele, were more frequent in patients with intractable GD than they were in controls and patients with GD in remission. Interestingly, the rs2300519 TT genotype and T allele, rs4903961 CC genotype and C allele, and rs179247 GG genotype, all of which are minor genotypes and alleles among the evaluated SNPs, were more frequent in HD patients than they were in controls, but there were no differences in the frequencies of these genotypes and alleles between patients with severe HD and mild HD. Among the evaluated SNPs, the rs4411444 GG genotype and the rs4903961 C allele in the enhancer regions of the TSHR gene were most strongly associated with the development of GD, especially intractable disease, and that of HD, respectively. Conclusions: Among the evaluated TSHR gene SNPs, the rs4411444 GG genotype and the rs4903961 C allele in the enhancer regions of the TSHR gene were most strongly associated with the development of GD, especially intractable disease, and that of HD, respectively.