Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012–1704) of the TSH receptor gene in Graves’ disease

Abstract

We determined the genetic variability of the 1st (CCC/ACC, P52T polymorphic variant) and 10th exons (bp 1012-1704) of the TSH receptor (TSHR) gene in Graves' disease. A total of 101 Graves' patients and 163 control subjects were screened. The A253 mutant allele was carried by nine patients with Graves' disease (8.91%) and 13 control subjects (7.98%) in heterozygous genotype. No significant difference in the frequency of the mutant allele was found between Graves' patients and control subjects. These results provide evidence that the A253 polymorphism has no genetic relevance in Graves' disease. Moreover, the DNA nucleotide sequence of 693 bp of the 10th exon (bp 1012-1704) of the TSHR gene was determined in 15 Graves' patients. Six patients were homozygous for the wild-type allele and nine were heterozygous for the mutant allele at the 253rd nucleotide of the first exon. No polymorphism was found in the DNA sequences obtained from leukocytes of Graves' patients, similarly to the sequences obtained from the nine control subjects. None of the nine patients carrying the A253 polymorphism in the 1st exon of the TSHR had polymorphism in the examined part of the 10th exon, including two additional patients whose thyroid tissue was directly analysed. In all likelihood, the polymorphisms of the examined regions of either the 1st or the 10th exon of the THSR gene do not contribute to the genetic susceptibility to Graves' disease.

Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population

“…In earlier studies using small sample sizes, three nonsynonymous SNPs, D36H, P52T and D727E, were claimed as susceptibility variants for GD in TSHR (19,27), but the associations have not been confirmed by subsequent studies (12,14,16,18,22). In this study, we did not find an association of the nonsynonymous SNPs P52T and D727E with GD in the Chinese Han population.…”

“…1b). Meanwhile, the SNPs in the coding region of TSHR, P52T (rs80491931) and D727E (rs80680336), which were associated with GD in previous studies using small samples (12,13,14,15,16,17,18,19,20), were not associated with GD in our study (Supplementary Table 5, see section on supplementary data given at the end of this article).…”

“…TSHR, on chromosome 14q31, was previously well established as a susceptibility locus for GD (12,13,14,15,16,17,18,19,20). However, the results of studies investigating the causal variants for GD in this region have been less consistent (21,22); single nucleotide polymorphisms (SNPs) in intron 7 have been suggested to be associated with GD in Japanese patients (21), but intron 1 SNPs have been found in association with GD in the Caucasian UK population (22,23).…”

“…However, the results of studies investigating the causal variants for GD in this region have been less consistent (21,22); single nucleotide polymorphisms (SNPs) in intron 7 have been suggested to be associated with GD in Japanese patients (21), but intron 1 SNPs have been found in association with GD in the Caucasian UK population (22,23). Further, early studies using small samples claimed that three nonsynonymous SNPs, D36H, P52T and D727E, in TSHR were associated with GD (12,13,14,15,16,17,18,19,20). In our most recent GWAS study, we have provided convincing evidence for the association of the SNPs in intron 1 of TSHR with GD in the Chinese Han population (8).…”

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

“…Association studies using three common TSHR exonic and nonsynonymous SNPs (in the extracellular and intracellular domain of the receptor) were inconsistent (5,6,(8)(9)(10)(11)(12). However, in two linkage studies we described a GD-specific chromosome 14 locus of *25 cM, designated GD-1 (4,7,13), in the center of which was the TSHR (between markers D14S258 and D14S1054).…”