title: Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, The Netherlands.
authors.forename: Monique H
authors.initials: MH
authors.lastname: Derikx
authors.affiliation: Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: 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.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Masson
authors.affiliation: 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.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruffert
authors.affiliation: Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, The Netherlands.
authors.forename: Rene H M
authors.initials: RH
authors.lastname: Te Morsche
authors.affiliation: Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Università Vita Salute San Raffaele e IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Giulia Martina
authors.initials: GM
authors.lastname: Cavestro
authors.affiliation: 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.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, The Netherlands.
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.affiliation: Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Zentralinstitut für Ernährungs- und Lebensmittelforschung (ZIEL) & Paediatric Nutritional Medicine, Technische Universität München (TUM), Munich, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.affiliation: Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
mesh_terms: D016022:Case-Control Studies; D057167:Claudins / Q000235:genetics*; D016001:Confidence Intervals; D005060:Europe; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D019512:Pancreatitis, Alcoholic / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D012737:Sex Factors; D016019:Survival Analysis; D014357:Trypsin / Q000235:genetics*; D014362:Trypsinogen / Q000235:genetics*
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; C523050:MORC4 protein, human; D009687:Nuclear Proteins; C064831:PRSS2 protein, human; D014362:Trypsinogen; C489303:PRSS1 protein, human; D014357:Trypsin
keywords: CHRONIC PANCREATITIS; GENETIC POLYMORPHISMS; PANCREATITIS; TRYPSINOGEN