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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.

顽固性免疫介导的眼部炎症疾病，包括白塞氏病和沃格特-小柳原田氏病，在发病时与 HLA 密切相关。首先，我们确定了HLA I类区域的完整碱基序列（1.9x10^6bp），以研究HLA区域的确切基因结构。利用该区域的微卫星，我们发现了758个由2-5个重复碱基组成的微卫星。此外，我们还利用以下种族的HLA I类区域的10个微卫星进行了白塞氏病的病因基因图谱；日本、希腊、伊朗、意大利、沙特阿拉伯、土耳其和中国。因此，成功地将病原基因缩小到MICA和HLA-B之间的46kb区域。此外，我们报道白塞氏病的病因基因存在于HLA-B基因附近。尤其是HLA-B51似乎与白塞病有显着的相关性。然后我们比较了患者和健康对照之间的 HLA-B51 及其启动子区域的碱基序列。结果，在内含子和启动子区域存在一些单核苷酸多态性（SNP）；然而，在白塞氏病中没有发现特定的 SNP。因此，表征 HLA-B51 的 SNP 可能与白塞氏病的遗传机制有关。此外，我们还检查了土耳其白塞氏病患者的 MICA 等位基因频率。结果，与健康对照相比，患者组的MICA^★009等位基因显着升高。 (R. R. = 7.1 p = 0.000046) 因此，有人认为MICA^★009- HLA^★51微型单倍型在白塞氏病的免疫遗传分子机制中起关键作用。其他炎症性眼部疾病的类似研究也在调查中。