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Nat Genet. 2015 May;47(5):518-522. doi: 10.1038/ng.3249. Epub 2015 Mar 16.

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.

Author information

1
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
2
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
3
Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
4
Pediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
5
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany.
6
Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
7
Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.
8
Etablissement Français du Sang (EFS)-Bretagne, Brest, France.
9
Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, Brest, France.
10
Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.
11
LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
12
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany.
13
Department of Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany.
14
Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
15
Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.
16
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
17
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany.
18
ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
19
Division of Endocrinology, Erasmus Hospital, Brussels, Belgium.
20
Department of Surgery, Universitätsklinikum Dresden, Dresden, Germany.
21
Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
22
Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
23
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
24
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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Contributed equally

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.

PMID:
25774637
PMCID:
PMC5321495
DOI:
10.1038/ng.3249
[Indexed for MEDLINE]
Free PMC Article

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