Studies on molecular genetic mechanism of intractable immune-mediated inflammatory diseases of the eye by genomic analyses

通过基因组分析研究难治性免疫介导的眼部炎症性疾病的分子遗传机制

基本信息

批准号：
12307038
负责人：
OHNO Shigeaki
金额：
$ 26.76万
依托单位：
HOKKAIDO UNIVERSITY (2001)Yokohama City University (2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Intractable immune-mediate inflammatory diseases of the eye including Behcet's disease and Vogt-Koyanagagi-Harada's disease are strongly associated with HLA on the onset. First, we determined whole base sequences of HLA-class I region (1.9x10^6bp) to investigate the exact gene structure of HLA region. As a result utilizing the microsatellites in the region, we found 758 microsatellites which composed of 2-5 repeated bases. Furthermore, we performed the etiological gene mapping of Behcet's disease with 10 microsatellites of HLA class I region in the following ethnics; Japanese, Greece, Iranian, Italian, Saudi Arabian, Turkish and Chinese. Consequently, the etiological gene was successly been be narrowed down to 46kb region between MICA and HLA-B. In addition, we reported that the etiological gene of Behcet's disease exists nearby HLA-B gene. Especially HLA-B51 seems to have a significant correlation with Behcet's disease. We then compared the base sequences of HLA-B51 and its promoter region between the patients and the healthy controls. As a result, there were some single nucleotide polymorphisms (SNPs) in the intron and promoter regions; however there was no specific SNPs found in Behcet's disease. Therefore, the SNPs which characterize HLA-B51 in common may work for the responsible genetic mechanism of Behcet's disease. Moreover, we examined MICA allele frequencies in Turkish patients with Behcet's disease. As a result, MICA^★009 allele was significantly elevated in the patients group compared with the healthy controls. (R. R. = 7.1 p = 0.000046) Therefore, it was suggested that MICA^★009- HLA^★51 mini-haplotype plays a key role in the immunogenetic molecular mechanisms of Behcet's disease.Similar studies are under investigation on other inflammatory ocular diseases.

眼睛包括Behcet疾病和Vogt-Koynagagi-Harada病在内的顽固性免疫 - 介入炎症疾病与HLA发作强烈相关。首先，我们确定了HLA级I区域（1.9x10^6bp）的整个碱基序列，以研究HLA区域的确切基因结构。结果，利用该地区的微卫星，我们发现了758个由2-5个重复碱基组成的微卫星。此外，我们在以下种族中使用了10个HLA I类区域的10微卫星的Behcet病的病因学基因映射。日本，希腊，伊朗，意大利语，沙特阿拉伯，土耳其语和中国人。因此，病因基因成功地缩小到云母和HLA-B之间的46kb区域。此外，我们报告说，贝塞特氏病的病因基因存在于HLA-B基因附近。特别是HLA-B51似乎与Behcet疾病有着显着的相关性。然后，我们比较了患者和健康对照组之间HLA-B51及其启动子区域的基本序列。结果，内含子和启动子区域中有一些单一的核苷酸多态性（SNP）。但是，在Behcet病中没有发现具体的SNP。因此，表征HLA-B51的SNP共同点可能适用于Behcet疾病的负责任遗传机制。此外，我们检查了土耳其贝塞氏病的云母等位基因频率。结果，与健康对照组相比，患者组的云母^★009等位基因显着升高。（R。R. = 7.1 P = 0.000046）因此，建议MICA^★009-HLA^★51 MINI-HAPLOTYPE在Behcet病的免疫遗传学分子机制中起关键作用。相似的研究对其他炎症性疾病进行了研究。