Monique H Derikx1, Peter Kovacs2, Markus Scholz3, Emmanuelle Masson4, Jian-Min Chen4, Claudia Ruffert5, Peter Lichtner6, Rene H M Te Morsche1, Giulia Martina Cavestro7, Claude Férec4, Joost P H Drenth1, Heiko Witt8, Jonas Rosendahl5. 1. Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, The Netherlands. 2. Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. 3. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. 4. Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France Etablissement Français du Sang (EFS)-Bretagne, Brest, France Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France. 5. Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany. 6. Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany. 7. Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Università Vita Salute San Raffaele e IRCCS Ospedale San Raffaele, Milan, Italy. 8. Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Zentralinstitut für Ernährungs- und Lebensmittelforschung (ZIEL) & Paediatric Nutritional Medicine, Technische Universität München (TUM), Munich, Germany.
Abstract
OBJECTIVE: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. DESIGN: We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. RESULTS: Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). CONCLUSIONS: The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. DESIGN: We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. RESULTS: Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). CONCLUSIONS: The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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