酒精性慢性胰腺炎易感基因筛选及鉴定研究

Chronic pancreatitis (CP) is a progressive inflammatory pancreatic disease, characterized by long course and recurrent attacks, resulting in poor life quality. Alcoholic CP is the main subtype of CP and such patients have definite history of alcohol intake. So far, the pathogenesis of alcoholic CP is still uncertain. We found that the prevalence of alcoholic CP caused by drinking was with obvious individual difference. As several studies has already shown that CP has certain genetic susceptibility, it's inferred that alcoholic CP may also be the same. However, the percentages of mutations,which have been proved to be involved in the pathogenesis of CP were very low, indicating that alcoholic CP is associated with other potential susceptible genes. So in the present study, peripheral venous blood samples from patients with alcoholic CP will be collected and whole exome sequencing will be conducted. Then according to the NCBI database, the sequencing results will be analysied by comparing with those from normal controls, which will identify the pathogenic mutations and susceptible genes. We will go further to verify the role of the newly identified susceptible genes in other patients with alcoholic CP and also with other subtypes of CP, deep into the gene function and explore the molecular mechanism or related cell signaling pathways. Our study will enrich the pathogenesis of alcoholic CP and show new insights into finding new therapy or preventions for CP.

慢性胰腺炎（CP）是一种胰腺组织进行性炎症性疾病，病程长、反复发作，严重影响患者生活质量。酒精性CP是最主要的一种类型，患者具有明确饮酒史。目前，酒精性CP发病机制尚不清楚。临床中我们发现酒精性CP发病具有显著个体差异，结合既往研究显示CP具有明确的遗传学发病基础，因此考虑上述个体差异与遗传易感性有关。然而，前期研究发现我国酒精性CP患者中已知易感基因的突变阳性率均较低，提示可能存在其他易感基因。本研究拟通过对我国酒精性CP和非胰腺疾病患者的外周血DNA进行全基因组外显子测序，借助生物信息学技术和基因组突变数据库，全面筛选致病突变，确定易感基因，在大规模酒精性CP和非酒精性CP样本群体中验证，并对该基因的功能进行深入挖掘，同时对其增加酒精性CP发病易感性的相关分子信号转导通路进行分析。明确酒精性CP易感基因和致病突变，丰富CP的发病机制研究，为今后预防和治愈CP提供新方向。

慢性胰腺炎（CP）是一种胰腺持续性炎症引起形态学不可逆改变和内外分泌功能损害的疾病，临床上缺乏有效治疗手段，生活质量低，给社会带来巨大公共医疗负担。酒精性CP 是CP主要的一种类型，患者具有明确饮酒史。目前，酒精性CP 发病机制尚不清楚，已知遗传因素其重要作用，但缺乏中国人群数据。前期我们成功收集酒精性慢性胰腺炎（350例）、非酒精性慢性胰腺炎患者（800例）和非胰腺疾病人群（1200例）的临床资料和外周静脉血标本。对1061例汉族CP患者和1196例汉族对照者进行四个CP相关基因（SPINK1, PRSS1, CTRC 和CFTR）的靶向二代测序，结果发现，致病基因型在ACP患者阳性率为39.8％，比非酒精性CP阳性率低；与突变阴性的患者相比，突变阳性患者的疾病发作中位年龄以及胰腺结石、糖尿病和脂肪泻的中位诊断年龄显著更早；研究也证实，SPINK1基因是酒精性CP的主要致病基因。为进一步明确SPINK1错义突变对CP的影响，我们开展相关研究。构建全长基因载体，证实24个突变中的4个（17％）与野生型相比显著降低了前体mRNA剪接和/或稳定性。申请者以通讯作者发表SCI共8篇，主编英文专著一部，获批专利2项，获得上海市银蛇奖一等奖以及上海市卫生系统新百人计划。