Endocrine Abstracts

The mechanisms triggering autoimmunity in the Graves-Basedow disease (GBD) are unknown, although the evidence for a genetic predisposition is well established. The thyrotropin receptor (TSHR) is a good candidate gene.

Objectives: To identify the main alleles/haplotypes of the TSHR gene, and to analyze the existence of TSHR susceptibility alleles to the GBD.

Material and methods: To establish the main alleles of TSHR gene, 54 polymorphisms (53 SNPs and 1 DIP) were selected including: 1) SNPs identified by sequencing both the promoter and 3′UTR regions, and 2) TagSNPs capturing most of the genetic variability of the gene. TagSNPs have been selected using the Haploview software and available data from HapMap project. These 54 polymorphisms were genotyped, using SNPlex technology, in 329 gDNA samples from: 192 control subjects and 137 GBD patients.

Results: In the case–control study of the 54 polymorphisms genotyped, after the multiple tests correction, a set of 10 SNPs showed a significantly different distribution between cases and controls (P<0.05), some of them with a high statistical signification (P=10⁻⁵). The odds ratio obtained ranged from 2.08 to 5.15. All these significant SNPs were located in a region that covers from the position −6200 in the promoter, to the intron 1, remaining the rest of the gene free of significant associations. Beyond this analysis of individual markers, the main haplotypes of the TSHR gene were established, using the different blocks of linkage disequilibrium (LD). Two highly significant haplotypes, one protective and one predisposing to the disease, were identified.

Conclusions: A set of SNPs located in the 5′ region of TSHR gene (from the promoter up to intron 1) significantly associated to GBD was identified. The existence of LD among the associated SNPs allow to define the main haplotypes, two of them conferring susceptibility or protection to the disease.