Chronic pancreatitis (CP) is an inflammatory disease characterized by agonizing pain, maldigestion and/or diabetes mellitus. The most serious complication is the development of pancreatic cancer, which is the fifth most frequent cause of cancer-related deaths worldwide.
Nearly 70 years ago, it was recognized for the first time that chronic pancreatitis clusters in selected families suggesting an inherited basis in these patients with “hereditary pancreatitis”. In 10-30 % of CP patients, no apparent underlying cause, including heredity, can be identified. Recent research indicates that a significant percentage of these patients with so-called "idiopathic chronic pancreatitis" also have a genetic basis for their disorder.
So far, in the majority of patients mutations in pancreatic digestive enzymes and their inhibitors are crucial pathogenic factors underlining the concept of a disturbed balance of proteases and their specific inhibitors in disease pathogenesis. Beside this imbalance, endoplasmic reticulum stress (ER stress) might be a second important mechanism as recently suggested for carboxypeptidase A1 (CPA1) mutations.
In the past, we investigated candidate genes using Sanger sequencing and identified several novel genes predisposing to CP. All known susceptibility genes to date account for only 50 % of hereditability in our paediatric cohort. Thus, several further disease causing genes have to exist. We aim to unveil new genetic factors predisposing to chronic inflammation of the pancreas and to characterize the underlying molecular mechanisms.
To identify these genes, we analyse our well characterised paediatric patient cohort by whole exome and whole genome sequencing, covering both, coding variants of the entire human exome and regulatory non-coding variation, which so far has not been performed in CP. Our paediatric group represents an optimal study population, since exogenic factors such as chronic alcohol abuse are absent. Our strategy will enable us to identify new pathways important for pancreatic inflammation beyond the protease/protease inhibitor system, which would be difficult to find by a candidate approach.
We will characterize the functional consequences of identified coding variants in vitro using recombinant proteins or CRISPR/Cas9 genome editing. By further merging non-coding next generation sequencing (NGS) findings with our recent genome-wide association study (GWAS) results, 1,000 genomes and Genome Aggregation Database (gnomAD) project as well as public domain data of epigenetic marks of regulatory regions we expect to identify regulatory non-coding variants, which are more and more considered as important contributors to disease risk. These variants will be functionally analysed using diverse approaches ranging from bioinformatics, interrogation of public domain gene regulatory data to proteomics and genome editing.
Our research translates basic biomedical research to a comprehension of pancreatic function in health and inflammation. It bridges latest generation DNA sequencing of well-defined patient samples and cutting-edge functional in vitro studies.
The decipherment of the genetic basis for idiopathic/hereditary pancreatitis will have a big impact on the understanding of commoner disease entities such as alcoholic pancreatitis and will also open additional avenues of research which might lead to novel therapeutics strategies.
- Prof Miklós Sahin-Tóth (Boston University, Boston, USA)
- Prof Claude Férec (INSERM, Brest, France)
- Prof Atsushi Masamune (Tohoku University, Sendai, Japan)
- Prof Matthias Löhr (Karolinska Institutet, Stockholm, Sweden)
- Prof Giriraj Chandak (CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India)
- Prof Mark Lowe (Washington University School of Medicine, St. Louis, USA)
- Prof Markus Schülke (Charité, Berlin, Germany)
- Dr Martin Seifert (Genomatix, Munich, Germany)
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