Association of Graves' Disease with Intragenic Polymorphism of the Thyrotropin Receptor Gene in a Cohort of Singapore Patients of Multi-Ethnic Origins

Abstract

Thyrotropin (TSH) receptor (TSHr) mutations have been investigated in relation to Graves' disease (GD) genetic susceptibility under the hypothesis that a modified antigen may have novel immunogenic properties. The prevalence of three germline polymorphisms--D36H, P52T, and D727E--were studied in a cohort of multiracial GD patients together with their associations with disease state, Graves' ophthalmopathy, and thyroid autoantibodies titers. Polymerase chain reaction products of exon 1 and 10e of the TSHr were generated from 164 GD patients (109 Chinese, 34 Malays, and 21 Indians) and 240 individuals with no thyroid illnesses (74 Chinese, 84 Malays, and 82 Indians). Mutations were detected by single-strand conformational polymorphism and confirmed with direct sequencing. The D36H mutation was absent, while significant ethnic differences in the distribution of the P52T and D727E mutations were found. The levels of thyroid autoantibodies also differed significantly amongst the three ethnic groups, with the Indian cohort having the lowest titer. Both the P52T and D727E mutations were not associated with GD. An intron mutation, C/G+63IVS1, was detected and showed significant association with GD. Overall, it conferred a twofold increase risk of GD, while subgroup analysis showed increased odds ratios of 2.4 for Chinese (p = 0.008) and 2.8 for Indian (p = 0.049) but not for the Malay ethnic group. Together with recent identification of disease susceptibility markers in the region of the TSHr gene, these results are supportive of genetic factors existing in this region that may be in linkage disequilibrium with the inheritance of various TSHr polymorphisms.

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

“…Hence, much effort was focused on linkage and association studies with nearby microsatellite marker and exonic SNP analyses of the receptor over the past 12 years. Our original description of GD-1 (4) and its further delineation (7,13), about 10.8 Mb from the TSHR gene, has now been further refined using TSHR intronic SNPs (17,18,19). These data suggest that it may The numbers represent individual subjects or alleles, with the percentage in parentheses.…”

“…Indeed, we and others have also shown previously that the thyroid cell expresses a variety of TSHR mRNA splice variants [for review see Graves and Davies (16)], indicating that SNPs or small RNAs in this intronic DNA may be important in the generation of different receptor forms and=or their control. Recently, a study from Singapore demonstrated an association of a TSHR intron 1 SNP with GD (17). SNPs in intron 7 of the TSHR were also found to be associated with GD in Japanese (18), and SNPs in intron 1 of the TSHR were reported to be associated with GD in Caucasians (19).…”

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

“…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).…”

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

“…Indeed, we and others (43,44) have also shown previously that the thyroid cell expresses a variety of TSHR mRNA splice variants, indicating that SNPs or small RNAs in this intronic DNA may be important in the generation of different receptor forms and/or their control. A study from Singapore first demonstrated an association of a TSHR intron 1 SNP with GD (45). SNPs in intron 7 of the TSHR were also found to be associated with GD in the Japanese (46), and SNPs in intron 1 of the TSHR were reported to be associated with GD in Caucasians (47).…”