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

par Fjeld, Karianne;Weiss, Frank U;Lasher, D;Rosendahl, J;Chen, JM;Johansson, BB;Kirsten, H;Ruffert, C;Masson, E;Steine, SJ;Bugert, Peter;Cnop, Miriam ;Grützmann, R;Mayerle, J;Mössner, J;Ringdal, M;Schulz, HU;Sendler, M;Simon, P;Torsvik, Janniche;Scholz, M.;Tjora, Erling;Férec, C;Witt, H;Lerch, Markus M;Njølstad, Pal R.;Johansson, S;Molven, Anders
Référence Nature genetics, 47, page (518-522)
Publication Publié, 2015

Article révisé par les pairs

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Résumé :

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.