Genome wide survey and functional analysis of autoimmune pancreatitis associated genes

自身免疫性胰腺炎是慢性胰腺炎的一种独特形式，其特征是胰腺实质肿胀、主胰管不规则狭窄、阻塞性黄疸、血清IgG浓度高、胰腺组织淋巴浆细胞浸润以及对皮质类固醇治疗的良好反应。我们以前发现，这种疾病与高血清IgG 4浓度和HLA DRB 1 ^*0405-DQB 1 ^*0401单倍型显著相关。然而，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物值较高，与补体激活系统的经典途径有关，而不是甘露糖结合凝集素途径或旁路途径。共发现18个微卫星标记，其中12个敏感标记和6个抗性标记分别位于第1、4、5、6、9、10、12、13、15、18号染色体和X染色体上。在这些标记附近，我们鉴定了一些候选的疾病相关基因。本研究阐明了自身免疫性胰腺炎在其活动期与补体激活系统的经典途径密切相关，并确定了一些可能的疾病相关基因。

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.