| Co-Investigator(Kenkyū-buntansha) |
MORIVAMA Kenji Seisan Kaihatsu Institute, Researcher, 研究員 (00301739)
SHIRASAWA Senji Kyushu Univ. Dept. of Bio. Defense Assist., 生体防御医学研究所, 助手 (10253535)
森山 賢治 財団法人生産開発科学研究所, 研究員 (00250217)
SALE Michele タスマニア大学, 生化学部, 講師
BOWDEN donal ボーマングレイ医科大学, 生化学部, 教授
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| Budget Amount *help |
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| 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
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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
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