| Research Abstract |
In a previous study (Sale et al., Proc. Assoc. Am. Physicians, 109 : 453, 1997) we identified a microsatellite marker near the thyrotropin receptor (TSHR) gene. Studies with this marker, TSHR-CA, revealed a significant association between AITD in Japanese and one specific allele (allele 1) of microsatellite sequence. In addition, weak evidence for association of AITD with two alleles of the CTLA-4 gene was observed. In the present study, TSHR-CA has been mapped to approximately 600kb of the TSHR gene using the radiation hybrid mapping. TSHR-CA and another TSHR microsatellite marker, TSHR-AT, which is located in intron 2 of TSHR gene (de Roux et al., Mol Cell Endocrinol, 117 : 253, 1996), were genotyped in a set of 349 unrelated Japanese AITD patients and 218 Japanese controls. Both the TSHR-CA and TSHR-AT markers showed association in this Japanese AITD population with a significant increase in alleles 1 (P=9.6×10ィイD1-4ィエD1), 2 (P=0.013) and 4 (P=0.046) of the TSHR-CA marker and allele
… More
s 5 (P=8.1×10ィイD1-9ィエD1) and 6 (P=8.4×10ィイD1-7ィエD1) of the TSHR-AT. The associations of allele 2 (P=0.04) of TSHR-CA, and allele 5 of TSHR-AT (P=2.9×10ィイD1-5ィエD1) were also significant in GD patients. The CTLA-4 gene, was also genotyped in this expanded set of Japanese AITD patients and con controls and association between AITD susceptibility and allele 2 (P=2.9×10ィイD1-8ィエD1) and allele 3 (P=2.5×10ィイD1-6ィエD1) were observed. The association of CTLA-4 allele 2 (P=2.9×10ィイD1-6ィエD1) and allele 3 (P=0.0009) with GD was also significant. More interestingly, the CTLA-4 allele 4 frequency was significantly decreased from 0.156 in the controls to 0.085 in the AITD patient population. This finding suggests a protective effect associated with allele 4. The presence of specific alleles of TSHR-CA, TSHR-AT, and CTLA-4 contribute significant increases of 1.4-1.8-fold for development of AITD. In summary, we found significant associations of AITD and GD with microsatellite markers for the TSHR gene and CTLA-4 in the Japanese population. These results confirm and expand upon our previous study suggesting that alleles of the TSHR and CTLA-4 genes, or genes near them contribute to AITD susceptibility and set the stage for future studies of interactions between these genes and AITD. Less
|
