Rosendahl, Jonas and Kirsten, Holger and Hegyi, Eszter and Kovacs, Peter and Weiss, Frank Ulrich and Laumen, Helmut and Lichtner, Peter and Ruffert, Claudia and Chen, Jian-Min and Masson, Emmanuelle and Beer, Sebastian and Zimmer, Constantin and Seltsam, Katharina and Alguel, Hana and Buehler, Florence and Bruno, Marco J. and Bugert, Peter and Burkhardt, Ralph and Cavestro, Giulia Martina and Cichoz-Lach, Halina and Farre, Antoni and Frank, Josef and Gambaro, Giovanni and Gimpfl, Sebastian and Grallert, Harald and Griesmann, Heidi and Gruetzmann, Robert and Hellerbrand, Claus and Hegyi, Peter and Hollenbach, Marcus and Iordache, Sevastitia and Jurkowska, Grazyna and Keim, Volker and Kiefer, Falk and Krug, Sebastian and Landt, Olfert and Di Leo, Milena and Lerch, Markus M. and Levy, Philippe and Loeffler, Markus and Loehr, Matthias and Ludwig, Maren and Macek, Milan and Malats, Nuria and Malecka-Panas, Ewa and Malerba, Giovanni and Mann, Karl and Mayerle, Julia and Mohr, Sonja and te Morsche, Rene H. M. and Motyka, Marie and Mueller, Sebastian and Mueller, Thomas and Noethen, Markus M. and Pedrazzoli, Sergio and Pereira, Stephen P. and Peters, Annette and Pfuetzer, Roland and Real, Francisco X. and Rebours, Vinciane and Ridinger, Monika and Rietschel, Marcella and Roesmann, Eva and Saftoiu, Adrian and Schneider, Alexander and Schulz, Hans-Ulrich and Soranzo, Nicole and Soyka, Michael and Simon, Peter and Skipworth, James and Stickel, Felix and Strauch, Konstantin and Stumvoll, Michael and Testoni, Pier Alberto and Toenjes, Anke and Werner, Lena and Werner, Jens and Wodarz, Norbert and Ziegler, Martin and Masamune, Atsushi and Moessner, Joachim and Ferec, Claude and Michl, Patrick and Drenth, Joost P. H. and Witt, Heiko and Scholz, Markus and Sahin-Toth, Miklos (2018) Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. GUT, 67 (10). pp. 1855-1863. ISSN 0017-5749, 1468-3288
Full text not available from this repository. (Request a copy)Abstract
Objective Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95%CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEREDITARY PANCREATITIS; CATIONIC TRYPSINOGEN; VARIANTS; PRSS1-PRSS2; GENE; INHIBITOR; MUTATION; Genome wide association study; chronic pancreatitis; genetic rearrangement |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Dec 2019 09:49 |
| Last Modified: | 09 Dec 2019 09:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13735 |
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