Deciphering the Missing Heritability in non-alcoholic Chronic Pancreatitis - (DeMissHer-CP-Study)

慢性胰腺炎（CP）是一种反复发作的炎症性疾病。患者遭受腹痛急性发作或持续疼痛，而外分泌和/或内分泌功能不全是常见的长期后果。CP患者患胰腺癌的风险高出约13倍。因此，CP代表了工业化国家患者以及医疗保健和社会系统的主要负担。虽然最常见的病因是酒精滥用，但在过去的三十年中，已经描述了与CP的几种遗传关联，这些遗传关联主要干扰蛋白酶及其消化酶级联抑制剂的平衡。为了确定遗传关联，已经应用了各种假设驱动和无假设的方法。然而，尽管所有这些努力，到目前为止，在高达50%的患者中没有检测到潜在的遗传改变。因此，很可能存在几种进一步的遗传关联。在这里，我们计划分析一个优秀的表型队列的300例早发性CP患者的外显子组测序显示没有潜在的遗传缺陷与全基因组测序。该队列是识别新的CP风险基因的理想选择。我们的方法与复制的数据在大型不相关的CP队列将使我们能够描述新的途径以外的迄今已知的基因。为了揭示相关变体的功能后果，我们将使用广泛的方法学技术，包括重组蛋白或CRISPR/Cas9基因组编辑。非编码变体将使用生物信息学工具进行研究，并询问蛋白质组学和基因编辑的公共领域基因调控数据。最后，我们有可能研究原发性外分泌胰腺类器官的离体变体，以了解CP发病机制的分子机制。我们的研究结果将对我们对胰腺炎症过程的理解产生重大影响，并在长期内导致新的治疗选择。

Chronic pancreatitis (CP) is a recurring inflammatory disease. Patients suffer from acute attacks of abdominal pain or from persisting pain while exocrine and/or endocrine insufficiency is a common long-term consequence. Patients with CP have an about 13-fold higher risk to develop pancreatic cancer. As such CP represents a major burden for patients as well as for healthcare and social systems in industrialized countries. Whereas the most common aetiological factor is alcohol misuse, several genetic associations with CP have been described in the last three decades that predominantly disturb the balance of proteases and their inhibitors of the digestive enzyme cascade. To identify genetic associations a variety of hypothesis-driven and hypothesis-free methods have been applied. However, despite all this efforts, in up to 50% of patients no underlying genetic alteration has been detected, so far. As such, several further genetic associations most likely exist. Here, we plan to analyse an excellently phenotyped cohort of 300 patients with early-onset CP in that exome sequencing revealed no underlying genetic defect with Whole-Genome Sequencing. This cohort is ideal to identify new CP risk genes. Our approach with replication of the data in large unrelated CP cohorts will enable us to describe new pathways beyond the hitherto known genes. To unveil the functional consequences of associated variants we will use a broad methodological spectrum of techniques including recombinant proteins or CRISPR/Cas9 genome editing. Non-coding variants will be investigated with bioinformatic tools with interrogation of public domain gene regulatory data to proteomics and gene editing. Lastly, we have the possibility to investigate variants ex vivo in primary exocrine pancreas organoids to understand the molecular mechanisms underlying CP pathogenesis. Our results will have a big impact on our understanding of pancreatic inflammatory processes and in the long-term lead to novel therapeutic options.