A Polymorphism in the Extracellular Domain of the Thyrotropin Receptor Is Highly Associated with Autoimmune Thyroid Disease in Females

Abstract

We and others have described previously a polymorphism at the first position of codon 52 (C52 --> A52) of the human thyrotropin receptor (hTSHr) gene. To determine its potential significance, we studied female (n = 100) and male (n = 25) patients with autoimmune thyroid disease (Graves' disease, n = 91; Hashimoto's thyroiditis, n = 34) and normal individuals [n = 121, female (n = 69), male (n = 52)]. Screening was performed using AciI restriction enzyme digestions of PCR-amplified genomic DNA. All codon 52 polymorphisms were verified by direct DNA sequencing. Data were analyzed using Chi-square or Fisher exact tests and p-values were corrected for multiple comparisons. Our studies demonstrated that this polymorphism is highly associated with autoimmune thyroid disease in the female population (corrected p = 0.008). We found no such association in the male population. Within females, there was a greater association between Graves' disease and the polymorphism (corrected p = 0.017) than between Hashimoto's thyroiditis and the polymorphism (corrected p = 0.090). The polymorphism was present in a higher proportion of Graves' disease patients with Graves' ophthalmopathy and pretibial dermopathy (40%) or Graves' ophthalmopathy, pretibial dermopathy, and acropachy (60%), than in patients with Graves' disease alone (15%), or Graves' disease and Graves' ophthalmopathy alone (17%). In conclusion, a polymorphism (C52 --> A52) of the hTSHr is associated with autoimmune thyroid disease in females.

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

“…All studies analyzing the TSHR-Pro52Thr or Asp36His variant showed no association, apart from one in which an association of the TSHR-Pro52Thr variant with Graves' disease was described in US Caucasian females (nZ100 females with autoimmune thyroid disease versus 69 controls) (29). These same authors later described two subjects who were homozygous for the Thr52 allele and had normal thyroid function tests, on the basis of which they suggested that the variant receptor is able to respond normally to TSH (23).…”

Association between thyroid stimulating hormone receptor gene intron polymorphisms and autoimmune thyroid disease in a Chinese Han population

“…For the suspicious cases of HT, diagnoses were confirmed by fine needle aspiration biopsies (FNAC). Another 242 controls were recruited from unrelated physical examination individuals in the Health Check-up Center of the Original studies on TSHR gene single nucleotide polymorphisms mainly concentrated on three polymorphic sites: two in exon1 (D36H and P52T) [24][25][26] and one in exon10 (D727E) [27,28]. However, most of them hardly confirmed the correlations.…”

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).…”