Molecular genetics and molecular epidemiology of intractable intraocular inflammation frequently found in Mongoloids for prevention of blindness.

蒙古人种中常见的难治性眼内炎症的分子遗传学和分子流行病学，用于预防失明。

• 批准号: 16406032
• 负责人: OHNO Shigeaki
• 金额: $ 8.45万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16406032/
• 关键词: intractable intraocular inflammation; uveitis; microsatellite; adenovirus; international surveillance; 国際サーペイランス; ベーチェット病; HLA; SNP; ヘルペスウイルス; PCR-Phylogenetic Analysis; 原田病

Epidemiologically, refractory intraocular inflammatory diseases such as Behcet's disease, Vogt-Koyanagi-Harada (VKH) disease and sarcoidosis have been believed to be common among the Mongoloid populations. In this study, we investigated these diseases from molecular biological and epidemiological aspects.As a result, we firstly found that the Behcet's disease was strongly associated with HLA-B locus genes. Furthermore we performed whole genome screening by utilizing 23,000 microsatellite markers, and identified 147 candidate loci (p<0.05). Among Korean patients with Behcet's disease, as well as Japanese patients, the frequency of HLA-B51 was significantly increased compared with healthy controls(p=0.0006). The genetic analysis of the melanocortine 5 receptor which was likely to be associated with Behcet's disease from animal models, did not show significant association in Japanese population.On the other hand, Vogt-Koyanagi-Harada disease was strongly associated with HLA-DRB1*0405 (p=- … More 0.000000079). But we did not find any association with VKH disease at following genes, such as tyrosinase, tyrosinase related protein 1 and tyrosinase related protein 2, respectively. However, we have found that the polymorphism of the interferon-gamma gene was significantly associated with integumentary findings of VKH disease (p=0.003).Epidemiologically, the distribution of Behcet's disease was around the East Asia, Eurasia, West Asia and the Mediterranean Sea. In contrast, Behcet's disease was rare in Europe, American continents and South-Middle Africa. These results were compatible with our previous findings, and suggested that this disease can be called as "Silk Road Disease". On the other hand, the distribution of VKH disease was mainly in South-East Asia, East Asia, North and Latin America. Regardless of the distribution, HLA-DR4 was strongly associated with VKH disease.We also investigated the molecular biology and epidemiology of adenoviral conjunctivitis, which is caused by extrinsic factors and without intrinsic factors. We found that the dominant serotype of adenovirus was different from one place to another. For example, the human AdV-type 4 was prevalent in the United Kingdom, human AdV-type 8 was prevalent in South-East Asia, and human AdV-type 37 was prevalent in Japan. These dominant serotypes were changing every 4 or 5 years and genome type mutation of the virus was constantly observed.These results suggest that refractory intraocular inflammation will be caused both by the intrinsic factors and extrinsic factors. Further studies on these etiological factors will clarify the true etiology, and develop new possible treatment for the prevention of blindness due to difficult intraocular inflammatory diseases. Less

流行病学上，难治性眼内炎性疾病，如白塞病，Vogt-Koyanagi-Harada（VKH）病和结节病已被认为是常见的蒙古人群。本研究从分子生物学和流行病学两个方面对白塞病进行了研究，首次发现白塞病与HLA-B位点基因密切相关。利用23，000个微卫星标记进行了全基因组筛选，共鉴定出147个候选位点（p<0.05）。在韩国白塞氏病患者，以及日本患者，HLA-B51的频率显着增加与健康对照组相比（p=0.0006）。黑皮质素5受体的遗传分析可能与来自动物模型的白塞氏病相关，但在日本人群中没有显示出显著的相关性。另一方面，Vogt-Koyanagi-Harada病与HLA-DRB 1 *0405强烈相关（p=- ...更多信息 0.000000079）。但在酪氨酸酶、酪氨酸酶相关蛋白1和酪氨酸酶相关蛋白2等基因上均未发现与VKH病相关的基因。然而，我们发现干扰素γ基因多态性与VKH病的皮肤表现显着相关（p=0.003）。从流行病学来看，白塞氏病分布在东亚、欧亚大陆、西亚和地中海。相比之下，白塞氏病在欧洲、美洲大陆和中南部非洲很少见。这些结果与我们以前的研究结果一致，并建议将这种疾病称为“丝绸之路病”。另一方面，VKH病主要分布在东南亚、东亚、北美洲和拉丁美洲。我们还研究了由外源性因素引起而非内源性因素引起的腺病毒性结膜炎的分子生物学和流行病学。我们发现腺病毒的优势血清型因地而异。例如，人AdV-4型在英国流行，人AdV-8型在东南亚流行，人AdV-37型在日本流行。这些优势血清型每4 ~ 5年发生一次变化，并不断观察到病毒基因组型的变异，提示难治性眼内炎症的发生可能是内因和外因共同作用的结果。对这些致病因素的进一步研究将有助于阐明其真正的病因，并为预防因眼内炎症性疾病而导致的失明开发新的可能的治疗方法。少

项目成果

Phosphorylation of p27(KIP1) in the developing retina and retinoblastoma.

发育中的视网膜和视网膜母细胞瘤中 p27(KIP1) 的磷酸化。

• 发表时间: 2005
• 期刊: Int.J.Mol.Med. 16・2
• 作者: Kase;S.et al.
• 通讯作者: S.et al.

ヘルスフードによる抗炎症作用.

保健食品的抗炎作用。

• 发表时间: 2006
• 期刊: Nano Ophthalmology 32
• 作者: Ochiai M R;Shimada Y;Konno T;Yamazaki S;Aoki K;Ohno S;Suzuki E;Ishiko H;Jin XH;Horie Y;Kitamura M;大野重昭;大野重昭
• 通讯作者: 大野重昭

Comparative study of two sets of critenia for the diagnosis of Vogt-Koyanagi-Haradas disease : Comparative study of two sets of criteria for the diagnosis of Vogt-Koyanagi-Haradas disease.

Vogt-Koyanagi-Haradas 病两套诊断标准的比较研究： Vogt-Koyanagi-Haradas 病两套诊断标准的比较研究。

• 发表时间: 2005
• 期刊: American Journal of Ophthalmology 139
• 作者: Ariga T;Shimada Y;Shiratori K;Ohgami K;Yamazaki S;Tagawa Y;Kikuchi M;Miyakita Y;Fujita K;Ishiko H;Aoki K;Ohno S;Goda C;Naka M;Kase S;Kase S;Saito W;Kase S;Shiratori K;Shiratori K;Kase S;Kitamura M
• 通讯作者: Kitamura M

Activation of nuclear factor-kappa B in the conjunctiva with the epithelial scraping of the mouse cornea and human epidemic keratoconjunctivitis

• DOI: 10.1136/bjo.2003.024646
• 发表时间: 2004-07-01
• 期刊: BRITISH JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.1
• 作者: Kase, S;Aoki, K;Yoshida, K
• 通讯作者: Yoshida, K

The cotton rat model for adenovirus ocular infection: antiviral activity of cidofovir

• DOI: 10.1016/j.antiviral.2003.08.003
• 发表时间: 2004-01-01
• 期刊: ANTIVIRAL RESEARCH
• 影响因子: 7.6
• 作者: Kaneko, H;Mori, S;Suzutani, T
• 通讯作者: Suzutani, T