低深度全基因组测序鉴定特发性慢性胰腺炎新基因及其功能研究

Chronic pancreatitis (CP) is a kind of persistent inflammatory disease of the pancreas, which could lead to irreversible changes in morphology and failure of exocrine and endocrine pancreatic function. It has brought a huge public medical burden to society. The etiology and pathogenesis of chronic pancreatitis is still uncertain, in which genetic factors play an important role as we know. Our previous study found that idiopathic chronic pancreatitis (ICP) accounts for a large proportion (> 70%) in Chinese CP patients. This study will collect all patients with idiopathic pancreatitis in our hospital. We have previously used the method of amplicon sequencing to perform exon sequencing analysis of four known susceptibility genes. In this study, we intend to use new high-throughput low-depth whole genome sequencing techniques to perform SNP screening for ICP patients who did not carry known mutations. Then, it will screen out SNP variation or rare pathogenic mutations with significant differences. Next, sequential validation will be performed in another 1,000 patients with idiopathic CP by Sanger sequencing. We will also explore the function of candidate genes and mutations to find its pathogenic mechanism. This study further supplement the clinical data, specimens and genetic resources of CP patients in China. Finally, a new theoretical basis and research methods will be provided for studying the genetic characteristics of CP patients in China and the early diagnosis and treatment of CP.

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，给社会带来了巨大的公共医疗负担，其发病机制亟待研究，遗传因素在其发病中发挥着重要作用。特发性慢性胰腺炎（ICP）病因不明确，在我国CP患者中所占比例极高（>70%）。本研究拟以我院所有特发性胰腺炎患者为研究对象，前期我们使用扩增子测序方法对4个已知易感基因进行外显子测序分析，对未携带已知突变的ICP患者，利用新的高通量低深度全基因组测序技术进行SNP筛选，筛选出显著差异的SNP变异或者罕见致病突变，运用sanger测序技术在另一批1000例特发性CP患者中进行重复验证。对候选基因和突变的功能进行初步探索，寻找其致病机制；从而进一步补充我国ICP患者临床资料、标本和遗传特征资源库，为研究中国CP患者易感基因特征、CP的早期诊断和治疗提供新的理论基础和研究方法。

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，给社会带来了巨大的公共医疗负担，其发病机制亟待研究。遗传因素在其发病中发挥着重要作用，但已知的易感基因仅能解释50%左右的患者，且中西方存在显著差异，因此，新的CP易感基因有待进一步发现和研究。本研究对464例CP患者和504例健康对照人群进行高通量低深度全基因组测序，筛选出显著差异的SNP变异或者罕见致病突变；通过国际合作明确CP候选易感基因相关SNP在中国人群的作用与差异；分析已知基因座PRSS1-PRSS2常见的SNP位点与饮酒剂量对CP的影响，明确弱环境因素与弱遗传因素在CP疾病中的作用；通过Gene-burden分析发现与CP相关的新基因TRPV6，通过功能学实验明确TRPV6功能缺失型突变与CP显著相关，并在动物实验中证实Trpv6敲除小鼠对雨蛙素刺激更敏感，证实TRPV6是CP新型易感基因。申请者以通讯作者发表SCI共12篇，获批1项发明专利，获得树兰医学青年奖、国家万人计划等人才项目。