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.
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