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

从流行病学角度来看，难治性眼内炎症性疾病如白塞氏病、Vogt-Koyanagi-Harada (VKH) 病和结节病被认为在蒙古人种人群中很常见。在本研究中，我们从分子生物学和流行病学方面对这些疾病进行了研究。结果，我们首次发现白塞氏病与HLA-B位点基因密切相关，并利用全基因组筛选。 23,000个微卫星标记，并鉴定出147个候选位点（p<0.05），在韩国白塞氏病患者以及日本患者中，与健康对照相比，HLA-B51的频率显着增加（p=0.0006）。从动物模型来看，黑皮质素 5 受体可能与白塞病有关，但在日本人群中并未显示出显着的关联。另一方面，Vogt-Koyanagi-Harada 病与 HLA-DRB1*0405 密切相关（p=- ​​… 更多 0.000000079），但我们没有发现以下基因与 VKH 病有任何关联，例如酪氨酸酶、酪氨酸酶相关蛋白 1 和然而，我们发现干扰素-γ基因的多态性显着相关。具有VKH病的外皮表现(p=0.003)。从流行病学来看，白塞病分布在东亚、欧亚大陆、西亚和地中海地区，而白塞病在欧洲、美洲大陆和中南半岛则很少见。这些结果与我们之前的发现相一致，表明该疾病可以称为“丝绸之路疾病”。另一方面，VKH 疾病的分布是。主要在东南亚、东亚、北美洲和拉丁美洲分布，HLA-DR4与VKH病密切相关。我们还调查了腺病毒结膜炎的分子生物学和流行病学，它是由外在因素引起的。我们发现不同地方腺病毒的优势血清型是不同的，例如在英国流行的是人AdV-4型，而在英国流行的是人AdV-8型。在东南亚，人类AdV 37型在日本流行。这些主要血清型每4或5年发生一次变化，并且不断观察到病毒的基因组类型突变。这些结果表明，难治性眼内炎症将由两者引起。对这些病因的进一步研究将阐明真正的病因，并开发新的可能的治疗方法来预防疑难眼内炎症性疾病导致的失明。

项目成果

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

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.

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

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

Disappearance of p27(KIP1) and increase in proliferation of the lens cells after extraction of most of the fiber cells of the lens

提取大部分晶状体纤维细胞后，p27(KIP1) 消失，晶状体细胞增殖增加

• 发表时间: 2005
• 期刊: Current Eye Research 30(6)
• 作者: Mandadi S;Tominaga T;他6名;Nakamura K.;Mitamura Y.;Kase S.
• 通讯作者: Kase S.