Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
| Autor: | James R. A. Skipworth, Sebastian Krug, Florence Bühler, Sebastian Gimpfl, Joachim Mössner, Anke Tönjes, Atsushi Masamune, Adrian Saftoiu, Roland H. Pfützer, Marcella Rietschel, Heiko Witt, Felix Stickel, Jens Werner, Peter Kovacs, Nicole Soranzo, Constantin Zimmer, Martin Ziegler, Helmut Laumen, Holger Kirsten, Marco J. Bruno, Joost P.H. Drenth, Markus M. Lerch, Markus M. Nöthen, Claus Hellerbrand, Annette Peters, Philippe Lévy, Jian-Min Chen, Monika Ridinger, Giulia Martina Cavestro, Emmanuelle Masson, Milena Di Leo, Peter Simon, Peter Bugert, Péter Hegyi, Karl Mann, Miklós Sahin-Tóth, Pier Alberto Testoni, Núria Malats, Rene H. M. te Morsche, Konstantin Strauch, Stephen P. Pereira, Josef Frank, Norbert Wodarz, Halina Cichoż-Lach, Jonas Rosendahl, Alexander Schneider, Marcus Hollenbach, Olfert Landt, Markus Löffler, Sergio Pedrazzoli, Volker Keim, Matthias Löhr, Marie Motyka, Sebastian Mueller, Ralph Burkhardt, Antoni Farré, Heidi Griesmann, Falk Kiefer, Giovanni Malerba, Claudia Ruffert, Markus Scholz, Francisco X. Real, Maren Ludwig, Eszter Hegyi, Harald Grallert, Hana Algül, Vinciane Rebours, Eva Rösmann, Frank Ulrich Weiss, Sonja Mohr, Robert Grützmann, Sevastitia Iordache, Michael Soyka, Milan Macek, Peter Lichtner, Patrick Michl, Claude Férec, Giovanni Gambaro, Michael Stumvoll, Katharina Seltsam, Thomas Müller, Grazyna Jurkowska, Ewa Małecka-Panas, Sebastian Beer, Julia Mayerle, Hans-Ulrich Schulz, Lena Werner |
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| Přispěvatelé: | Publica, Rosendahl, Jona, Kirsten, Holger, Hegyi, Eszter, Kovacs, Peter, Weiss, Frank Ulrich, Laumen, Helmut, Lichtner, Peter, Ruffert, Claudia, Chen, Jian min, Masson, Emmanuelle, Beer, Sebastian, Zimmer, Constantin, Seltsam, Katharina, Algül, Hana, Bühler, Florence, Bruno, Marco J, Bugert, Peter, Burkhardt, Ralph, Cavestro, GIULIA MARTINA, Cichoz lach, Halina, Farré, Antoni, Frank, Josef, Gambaro, Giovanni, Gimpfl, Sebastian, Grallert, Harald, Griesmann, Heidi, Grützmann, Robert, Hellerbrand, Clau, Hegyi, Péter, Hollenbach, Marcu, Iordache, Sevastitia, Jurkowska, Grazyna, Keim, Volker, Kiefer, Falk, Krug, Sebastian, Landt, Olfert, Leo, Milena Di, Lerch, Markus M, Lévy, Philippe, Löffler, Marku, Löhr, Matthia, Ludwig, Maren, Macek, Milan, Malats, Nuria, Malecka panas, Ewa, Malerba, Giovanni, Mann, Karl, Mayerle, Julia, Mohr, Sonja, Te Morsche, Rene H. M, Motyka, Marie, Mueller, Sebastian, Müller, Thoma, Nöthen, Markus M, Pedrazzoli, Sergio, Pereira, Stephen P, Peters, Annette, Pfützer, Roland, Real, Francisco X, Rebours, Vinciane, Ridinger, Monika, Rietschel, Marcella, Rösmann, Eva, Saftoiu, Adrian, Schneider, Alexander, Schulz, Hans ulrich, Soranzo, Nicole, Soyka, Michael, Simon, Peter, Skipworth, Jame, Stickel, Felix, Strauch, Konstantin, Stumvoll, Michael, Testoni, PIER ALBERTO, Tönjes, Anke, Werner, Lena, Werner, Jen, Wodarz, Norbert, Ziegler, Martin, Masamune, Atsushi, Mössner, Joachim, Férec, Claude, Michl, Patrick, Joost, P. H. Drenth, Witt, Heiko, Scholz, Marku, Sahin tóth, Miklós, Gastroenterology & Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Linkage disequilibrium medicine.medical_specialty Settore MED/12 - GASTROENTEROLOGIA Population Genome Wide Association Study Chronic Pancreatitis Genetic Rearrangement Locus (genetics) Single-nucleotide polymorphism Genome-wide association study Biology Gastroenterology chronic pancreatitis 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center Internal medicine Genetic predisposition medicine Allele education Genetics education.field_of_study medicine.disease ddc genetic rearrangement Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] 030104 developmental biology Genome wide association study Pancreatitis chronic pancreatiti Chronic pancreatitis Genetic rearrangement |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname Gut 67, 1855–186 (2018) Gut, 67, 1855-1863 Gut, 67, 10, pp. 1855-1863 Gut, 67(10), 1855-1863. BMJ Publishing Group |
| ISSN: | 0017-5749 |
| Popis: | ObjectiveAlcohol-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.Design1959 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.ResultsWe 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 16.6 kb 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.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders. |
| Databáze: | OpenAIRE |
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