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

作者：Fjeld Karianne; Weiss Frank Ulrich; Lasher Denise; Rosendahl Jonas; Chen Jian Min; Johansson Bente B; Kirsten Holger; Ruffert Claudia; Masson Emmanuelle; Steine Solrun J; Bugert Peter; Cnop Miriam; Gruetzmann Robert; Mayerle Julia; Moessner Joachim; Ringdal Monika; Schulz Hans Ulrich; Sendler Matthias; Simon Peter; Sztromwasser Pawel; Torsvik Janniche; Scholz Markus; Tjora Erling; Ferec Claude; Witt Heiko; Lerch Markus M; Njolstad Pal R; Johansson Stefan

来源：Nature Genetics, 2015, 47(5): 518-U121.

DOI：10.1038/ng.3249

Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene(1). Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dys2). 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 x 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 x 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.

• 出版日期2015-5
• 单位河北医科大学