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- Title
A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.
- Authors
Fjeld, Karianne; Johansson, Bente B; Ringdal, Monika; Torsvik, Janniche; Johansson, Stefan; Bugert, Peter; Cnop, Miriam; Grützmann, Robert; Schulz, Hans-Ulrich; Sztromwasser, Paweł; Scholz, Markus; Tjora, Erling; Njølstad, Pål R; Férec, Claude; Molven, Anders; Weiss, Frank Ulrich; Mayerle, Julia; Sendler, Matthias; Simon, Peter; Lerch, Markus M
- 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.
- Subjects
GENETICS of pancreatitis; EXOCRINE glands; PANCREATIC enzymes; GENETICS of diabetes; TYPE 2 diabetes; DISEASES
- Publication
Nature Genetics, 2015, Vol 47, Issue 5, p518
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.3249