BACKGROUND: A large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms. METHODS: We used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians). RESULTS: The allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP. CONCLUSIONS: These results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
BACKGROUND: A large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms. METHODS: We used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians). RESULTS: The allele and genotype frequencies from GDpatients, but not HTpatients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GDpatients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP. CONCLUSIONS: These results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
Authors: K Sakai; S Shirasawa; N Ishikawa; K Ito; H Tamai; K Kuma; T Akamizu; M Tanimura; K Furugaki; K Yamamoto; T Sasazuki Journal: Hum Mol Genet Date: 2001-06-15 Impact factor: 6.150
Authors: Sabine Amsellem; Dorothée Briffaut; Alain Carrié; Jean Pierre Rabès; Jean Philippe Girardet; Alexandre Fredenrich; Philippe Moulin; Michel Krempf; Yves Reznik; Bernard Vialettes; Jean Luc de Gennes; Eric Brukert; Pascale Benlian Journal: Hum Genet Date: 2002-09-13 Impact factor: 4.132
Authors: R Villanueva; A M Inzerillo; Y Tomer; G Barbesino; M Meltzer; E S Concepcion; D A Greenberg; N MacLaren; Z S Sun; D M Zhang; S Tucci; T F Davies Journal: Thyroid Date: 2000-09 Impact factor: 6.568
Authors: Yaron Tomer; Yoshiyuki Ban; Erlinda Concepcion; Giuseppe Barbesino; Ronald Villanueva; David A Greenberg; Terry F Davies Journal: Am J Hum Genet Date: 2003-09-12 Impact factor: 11.025
Authors: Francesca Pastore; Antonio Martocchia; Manuela Stefanelli; Pietro Prunas; Stefania Giordano; Lavinia Toussan; Antonio Devito; Paolo Falaschi Journal: World J Hepatol Date: 2016-01-18
Authors: Yaron Tomer; Alia Hasham; Terry F Davies; Mihaela Stefan; Erlinda Concepcion; Mehdi Keddache; David A Greenberg Journal: J Clin Endocrinol Metab Date: 2012-11-01 Impact factor: 5.958