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Genome wide survey and functional analysis of autoimmune pancreatitis associated genes

自身免疫性胰腺炎相关基因的全基因组调查和功能分析

基本信息

批准号：
16390205
负责人：
KAWA Shigeyuki
金额：
$ 9.22万
依托单位：
Shinshu 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 2005
项目状态：
已结题

项目摘要

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by swelling of the pancreatic parenchyma, irregular narrowing of the main pancreatic duct, obstructive jaundice, high serum IgG concentration, lymphoplasmacytic infiltration in the pancreatic tissue and favorable response to corticosteroid therapy. We previously revealed that this disease is significantly associated with high serum IgG4 concentration and HLA DRB1^*0405-DQB1^*0401 haplotype. However, pathogenesis has not been fully elucidated. The aim of the present study was to clarify whether mannose binding pathway of complement activation system is operating in the pathogenesis, and to survey genome wide analysis of autioimmune pancreatitis associated genes using microsatellite markers covering entire chromosome. The results showed that autoimmune pancreatitis exhibits a high serum circulating immune complex values in its active stage, which links to a complement activation system with a classical pathway, rather than the mannose-binding lectin pathway or alternative pathway. We found 18 associated microsatellite markers, 12 sensitive and 6 resistant, which exist in chromosome 1, 4, 5, 6, 9, 10, 12, 13, 15, 18 and X. Near the these markers, we identified some candidate disease associated genes. In conclusion, we clarified that autoimmune pancreatitis is closely associated with classical pathway of complement activation system in its active stage, and identified some candidate disease associated genens.

自身免疫性胰腺炎是一种独特的慢性胰腺炎，其特征是胰腺实质肿胀，主胰管不规则狭窄，梗阻性黄疸，血清免疫球蛋白水平升高，胰腺组织淋巴浆细胞浸润，对糖皮质激素治疗反应良好。我们先前发现本病与血清高IgG4浓度和HLADRB1^*0405-DQB1^*0401单倍型显著相关。然而，其发病机制尚未完全阐明。本研究的目的是阐明补体激活系统的甘露糖结合途径是否在自身免疫性胰腺炎的发病机制中起作用，并利用覆盖整个染色体的微卫星标记对自身免疫性胰腺炎相关基因进行全基因组分析。结果表明，自身免疫性胰腺炎活动期血清循环免疫复合体值较高，与补体激活系统以经典途径相连，而不是甘露糖结合凝集素途径或替代途径。在1、4、5、6、9、10、12、13、15、18和X染色体上发现了18个相关微卫星标记，其中12个是感病基因，6个是抗病基因，在这些标记附近还发现了一些与疾病相关的候选基因。综上所述，我们明确了自身免疫性胰腺炎与活动期补体激活系统的经典途径密切相关，并确定了一些候选的疾病相关基因。