Research into the Genetics of Autoimmune Thyroid Disease

自身免疫性甲状腺疾病的遗传学研究

• 批准号: 10044273
• 负责人: AKAMIZU Takashi
• 金额: $ 5.57万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10044273/
• 关键词: Graves'disease; genetic factor; microsatellite; TSH receptor; CTLA-4; autoimmune thyroid disease; バセドウ病

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

在先前的研究中（Sale等，Proc。Assoc。Am。Am。Am.Am。Bysicians，109：453，1997），我们在甲状腺激素受体（TSHR）基因附近鉴定了一个微卫星标记。使用该标记的研究TSHR-CA的研究表明，日本AITD与微卫星序列的一个特定等位基因（等位基因1）之间存在显着关联。此外，观察到AITD与CTLA-4基因的两个等位基因的关联证据较弱。在本研究中，使用辐射杂种映射将TSHR-CA映射到大约600KB的TSHR基因。 TSHR-CA和另一个TSHR微卫星标记TSHR-AT位于TSHR基因的内含子2中（De Roux等，Mol Cell Endocrinol，117：253，1996），在349个无关的日本AITD患者和218个日本对照组中进行了基因型。 Both the TSHR-CA and TSHR-AT markers shown association in this Japanese AITD population with a significant increase in alleles 1 (P=9.6×10 Ii D1-4i D1), 2 (P=0.013) and 4 (P=0.046) of the TSHR-CA marker and allele … More s 5 (P=8.1×10 Ii D1-9i D1) and 6 (P=8.4×10 Ii TSHR-AT的D1-7i D1）。 TSHR-CA等位基因2（P = 0.04）的关联和TSHR-AT的等位基因5（P = 2.9×10 D1-5 E D1）在GD患者中也很重要。 CTLA-4基因也在这组扩展的日本AITD患者和CON对照组和AITD敏感性和等位基因2（P = 2.9×10 D1-8 E D1）和等位基因3（P = 2.5×10 D1-6 E D1）之间进行了基因分型。 CTLA-4等位基因2（P = 2.9×10 D1-6 D1）和等位基因3（P = 0.0009）与GD的关联也很重要。更有趣的是，CTLA-4等位基因4频率从对照组的0.156显着降低到AITD患者人群的0.085。这一发现表明与等位基因4相关的保护作用。TSHR-CA，TSHR-AT和CTLA-4的特定等位基因的存在，在AITD的开发中造成了1.4-1.8倍的显着增加。总而言之，我们在日本人群中发现了AITD和GD与TSHR基因和CTLA-4的微卫星标记的显着关联。这些结果证实并扩展了我们先前的研究，表明TSHR和CTLA-4基因的等位基因或附近的基因有助于AITD敏感性，并为这些基因与AITD之间相互作用的未来研究奠定了基础。较少的

项目成果

Akamizu.T: "Characterization of recombinant monoclonal anti-thyrotropin receptor antibodies (TSHRAbs)deriyed from lymphocytes of nalients with Graves disease: Epitope and binding study of two stinfulatory TSHRAbs." Endocrinology,1999. ((in press))

Akamizu.T：“从格雷夫斯病患者淋巴细胞中提取的重组单克隆抗促甲状腺素受体抗体 (TSHRAb) 的表征：两种刺激性 TSHRAb 的表位和结合研究。”

Akamizu T.,Sale MM.,Rich SS.,Hiratani H.,Yoshimura Noh J.,Saijo M.,et al.: "Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients"J Endocrinol Invest. 22:Suppl.. 105 (1999)

Akamizu T.、Sale MM.、Rich SS.、Hiratani H.、Yoshimura Noh J.、Saijo M.等人：“日本患者自身免疫性甲状腺疾病与促甲状腺素受体基因和 CTLA-4 微卫星标记的关联

Moriyama.K: "Preparation and functional analysis of recombinant inhibitory anti-TSH receptor antibodies involved in pr9mary hypothyroidism." Proceedings of The 71th meeting of the American Thyroid Association,Portland,Oregon. (abstract). 81 (1998)

Moriyama.K：“涉及原发性甲状腺功能减退症的重组抑制性抗 TSH 受体抗体的制备和功能分析。”

Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Kamitani S, Harada M, Ishikawa M, Kuwahara K, Ogawa E, Hamanaka I, Takahashi N, Ogawa E, Hamanaka I, Takahashi N, Kaneshige T, Teraoka H, Akamizu T, Azuma N, Yoshimasa Y, Yoshimasa T,

宫本 Y、齐藤 Y、梶山 N、吉村 M、岛崎 Y、中山 M、神谷 S、原田 M、石川 M、桑原 K、小川 E、滨中 I、高桥 N、小川 E、滨中 I、高桥 N、金茂 T

Koshiyama H.,Sellitti DF.,Doi SQ.,Akamizu T.,Nakao K.: "Comment on Thyrotropin Receptor Gene and Mitral Valve Prolapse"J Clin Endocrinol Metab. 84. 3404 (1999)

Koshiyama H.，Sellitti DF.，Doi SQ.，Akamizu T.，Nakao K.：“促甲状腺激素受体基因和二尖瓣脱垂的评论”J Clin Endocrinol Metab。