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

• Applicants: Dr. Tobias Bernd Ludwig Haack; Professor Dr. Jonas Rosendahl
• Subject Area: Gastroenterology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433158657

• Final Report Year: 2025

Final Report Abstract

Chronic pancreatitis is a recurring inflammatory disease. The most common cause is harmful alcohol consumption. Genetic causes of chronic pancreatitis have been known for several decades. These have been identified, particularly in patients with an early onset of the disease. Nevertheless, the cause of the disease remains unclear in a large proportion of patients. To identify new genetic alterations as a cause of chronic pancreatitis in this cohort, we performed whole genome sequencing. This method can be used to identify changes in all sections of the genome. Our analyses confirmed known pancreatitis risk genes such as CFTR, SPINK1, and PNLIP. New genetic associations were identified, for example in transcription factors. In addition, major genetic rearrangements were identified in known chronic pancreatitis genes such as CTRC, which may explain the pathogenesis in individual patients.

Publications

• Analysis of GPRC6A variants in different pancreatitis etiologies. Pancreatology, 20(7), 1262-1267.
  Kaune, Tom; Ruffert, Claudia; Hesselbarth, Nico; Damm, Marko; Krug, Sebastian; Cardinal von Widdern, Julian; Masson, Emmanuelle; Chen, Jian-Min; Rebours, Vinciane; Buscail, Louis; Férec, Claude; Grützmann, Robert; te Morsche, Rene H.M.; Drenth, Joost PH.; Cavestro, Giulia Martina; Zuppardo, Raffaella Alessia; Saftoiu, Adrian; Malecka-Panas, Ewa; Głuszek, Stanislaw ... & Rosendahl, Jonas
  
• Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis. Pancreatology, 20(8), 1598-1603.
  Seltsam, Katharina; Pentner, Carola; Weigl, Franziska; Sutedjo, Stella; Zimmer, Constantin; Beer, Sebastian; Bugert, Peter; Ewers, Maren; Ruffert, Claudia; Michl, Patrick; Laumen, Helmut; Witt, Heiko & Rosendahl, Jonas
  
• The three common polymorphisms p.A986S, p.R990G and p.Q1011E in the calcium sensing receptor (CASR) are not associated with chronic pancreatitis. Pancreatology, 21(7), 1299-1304.
  Ewers, Maren; Canaff, Lucie; Weh, Antonia EM.; Masson, Emmanuelle; Eiseler, Katharina; Chen, Jian-Min; Rebours, Vinciane; Bugert, Peter; Michl, Patrick; Rosendahl, Jonas; Férec, Claude; Goltzman, David & Witt, Heiko
  
• Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms. Pancreatology, 22(4), 449-456.
  Schmidt, Andreas W.; Kühnapfel, Andreas; Kirsten, Holger; Grallert, Harald; Hellerbrand, Claus; Kiefer, Falk; Mann, Karl; Mueller, Sebastian; Nöthen, Markus M.; Peters, Annette; Ridinger, Monika; Frank, Josef; Rietschel, Marcella; Soranzo, Nicole; Soyka, Michael; Wodarz, Norbert; Malerba, Giovanni; Gambaro, Giovanni; Gieger, Christian ... & Rosendahl, Jonas
  
• Genetic analysis of pancreatic phospholipase A2 (PLA2G1B) in patients with chronic pancreatitis. Pancreatology, 22(2), 244-247.
  Ewers, Maren; Epple, Denise; Bugert, Peter; Rosendahl, Jonas & Witt, Heiko
  
• Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis. Pancreas, 51(9), 1231-1234.
  Neubauer, Claudia; Ewers, Maren; Schulz, Hans-Ulrich; Weiß, Frank Ulrich; Lämmerhirt, Felix; Lerch, Markus M.; Bugert, Peter; Landt, Olfert; Algül, Hana; Rosendahl, Jonas & Witt, Heiko
  
• Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis. Pancreatology, 22(6), 713-718.
  Tóth, Andrea; Demcsák, Alexandra; Zankl, Florence; Oracz, Grzegorz; Unger, Lara Sophie; Bugert, Peter; Laumen, Helmut; Párniczky, Andrea; Hegyi, Péter; Rosendahl, Jonas; Gambin, Tomasz; Płoski, Rafał; Koziel, Dorota; Gluszek, Stanisław; Lindgren, Fredrik; Löhr, J. Matthias; Sahin-Tóth, Miklós; Witt, Heiko; Rygiel, Agnieszka Magdalena ... & Hegyi, Eszter
  
• Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene. Pancreatology, 22(5), 564-571.
  Rygiel, Agnieszka Magdalena; Unger, Lara Sophie; Sörgel, Franziska Lena; Masson, Emmanuelle; Matsumoto, Ryotaro; Ewers, Maren; Chen, Jian-Min; Bugert, Peter; Buscail, Louis; Gambin, Tomasz; Oracz, Grzegorz; Winiewska-Szajewska, Maria; Mianowska, Agnieszka; Poznanski, Jarosław; Kosińska, Joanna; Stawinski, Piotr; Płoski, Rafał; Koziel, Dorota; Gluszek, Stanisław ... & Witt, Heiko
  
• Genetic and functional analysis of chymotrypsin-like protease (CTRL) in chronic pancreatitis. Pancreatology, 23(8), 957-963.
  Eiseler, Katharina; Neppl, Lea; Schmidt, Andreas W.; Rauscher, Beate; Ewers, Maren; Masson, Emmanuelle; Chen, Jian-Min; Férec, Claude; Rebours, Vinciane; Grammatikopoulos, Tassos; Foskett, Pierre; Greenhalf, William; Halloran, Christopher; Neoptolemos, John; Haack, Tobias B.; Ossowski, Stephan; Sturm, Marc; Rosendahl, Jonas; Laumen, Helmut & Witt, Heiko
  
• Risk of chronic pancreatitis in carriers of the c.180C>T (p.Gly60=) CTRC variant: case-control studies and meta-analysis. Pancreatology, 23(5), 481-490.
  Berke, Gergő; Beer, Sebastian; Gede, Noémi; Takáts, Amanda; Szentesi, Andrea; Hegyi, Péter; Rosendahl, Jonas; Sahin-Tóth, Miklós; Németh, Balázs Csaba & Hegyi, Eszter