A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis
Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction2. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
16 March 2015
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| In: |
Nature genetics
Year: 2015, Volume: 47, Issue: 5, Pages: 518-522 |
| ISSN: | 1546-1718 |
| DOI: | 10.1038/ng.3249 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1038/ng.3249 Verlag, Volltext: https://www-nature-com.ezproxy.medma.uni-heidelberg.de/articles/ng.3249 
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| Author Notes: | Karianne Fjeld, Frank Ulrich Weiss, Denise Lasher, Jonas Rosendahl, Jian-Min Chen, Bente B. Johansson, Holger Kirsten, Claudia Ruffert, Emmanuelle Masson, Solrun J. Steine, Peter Bugert, Miriam Cnop, Robert Grützmann, Julia Mayerle, Joachim Mössner, Monika Ringdal, Hans-Ulrich Schulz, Matthias Sendler, Peter Simon, Paweł Sztromwasser, Janniche Torsvik, Markus Scholz, Erling Tjora, Claude Férec, Heiko Witt, Markus M. Lerch, Pål R. Njølstad, Stefan Johansson and Anders Molven |
| Summary: | Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction2. 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. |
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| Item Description: | Gesehen am 30.11.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1546-1718 |
| DOI: | 10.1038/ng.3249 |