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

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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.