title: A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.
abstract: Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10(-6) by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 × 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Karianne
authors.initials: K
authors.lastname: Fjeld
authors.affiliation: Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.affiliation: Pediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.|Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Lasher
authors.affiliation: Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
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, Brest, France.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bente B
authors.initials: BB
authors.lastname: Johansson
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
authors.affiliation: Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.|Department of Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany.|Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruffert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, 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: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Solrun J
authors.initials: SJ
authors.lastname: Steine
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.|Division of Endocrinology, Erasmus Hospital, Brussels, Belgium.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
authors.affiliation: Department of Surgery, Universitätsklinikum Dresden, Dresden, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.affiliation: Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Monika
authors.initials: M
authors.lastname: Ringdal
authors.affiliation: Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schulz
authors.affiliation: Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Simon
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
authors.forename: Paweł
authors.initials: P
authors.lastname: Sztromwasser
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Janniche
authors.initials: J
authors.lastname: Torsvik
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Erling
authors.initials: E
authors.lastname: Tjora
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, 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: Pediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.|Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.affiliation: Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.|Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
mesh_terms: D000437:Alcoholism / Q000150:complications / Q000201:enzymology / Q000235:genetics; D000595:Amino Acid Sequence; D043182:Carboxylesterase / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics*; D008297:Male; D050500:Pancreatitis, Chronic / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic
chemical_list: D043182:Carboxylesterase; C054621:CEL protein, human; D008049:Lipase