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。患者遭受急性腹痛发作或持续性疼痛，而外分泌和/或内分泌不足是常见的长期后果。患有CP的患者患胰腺癌的风险大约是后者的13倍。因此，CP对患者以及工业化国家的医疗保健和社会制度来说都是一个主要负担。虽然最常见的致病因素是酒精滥用，但在过去的30年里，已经描述了几种与CP有关的基因，这些基因主要扰乱了消化酶级联的蛋白酶及其抑制物之间的平衡。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，尽管做出了所有这些努力，到目前为止，在多达50%的患者中还没有检测到潜在的基因改变。因此，很可能存在几个更深层次的遗传关联。在这里，我们计划分析300名早发性CP患者的优秀表型队列，因为外显子组测序显示全基因组测序没有潜在的遗传缺陷。这一队列是识别新的CP风险基因的理想方法。我们在大型无关CP队列中复制数据的方法将使我们能够描述迄今已知基因之外的新途径。为了揭示相关变异的功能后果，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。将使用生物信息学工具对非编码变体进行研究，并询问公共领域的基因调控数据，以进行蛋白质组学和基因编辑。最后，我们有可能在体外研究初级外分泌胰腺器官的变异体，以了解CP发病的分子机制。我们的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.