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

Abstract

Carboxyl-ester lipase is a digestive pancreatic enzyme encoded by the highly polymorphic CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young (MODY) with pancreatic exocrine dysfunction2. Here we identified a hybrid allele (CEL-HYB), originating from a crossover between CEL and its neighboring pseudogene CELP. In a discovery cohort of familial chronic pancreatitis cases, the carrier frequency of CEL-HYB was 14.1% (10/71) compared with 1.0% (5/478) in controls (odds ratio [OR] = 15.5, 95% confidence interval [CI] = 5.1-46.9, P = 1.3 × 10−6). Three replication studies in non-alcoholic chronic pancreatitis cohorts 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 revealed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. The hybrid variant of CEL is the first chronic pancreatitis gene identified outside the protease/antiprotease system of pancreatic acinar cells.

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

“…Gene conversion events between PRSS1 and PRSS2 or between PRSS1 and the pseudogene PRSS3P2 were shown to generate pathogenic alleles that cause hereditary pancreatitis [19][20][21]. More recently, a recombination allele of the carboxyl ester lipase gene (CEL) and its pseudogene CELP was described as a novel genetic risk factor for CP [22]. Finally, conversion events between the SBDS gene and its paralogous duplicated pseudogene SBDSP cause Shwachman-Bodian-Diamond syndrome, an autosomal recessive disorder with pancreatic exocrine insufficiency, hematologic dysfunction, and skeletal abnormalities [23].…”

Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis

“…chronic pancreatitis; hereditary pancreatitis; trypsinogen activation; autoactivation; endoplasmic reticulum stress; misfolding; intracellular aggregation CHRONIC PANCREATITIS IS A relapsing progressive inflammatory disease of the pancreas that often develops on the basis of genetic predisposition (7,44). Susceptibility genes identified to date include, in the order of discovery, PRSS1 (serine protease 1, human cationic trypsinogen), CFTR (cystic fibrosis transmembrane conductance regulator), SPINK1 (serine protease inhibitor Kazal type 1, pancreatic secretory trypsin inhibitor), CTRC (chymotrypsinogen C), CPA1 (procarboxypeptidase A1), and CEL (carboxyl ester lipase) (8,12,26,31,42,45,46). Mutations in PRSS1, such as p.N29I and p.R122H, are strong risk factors that cause autosomal dominant hereditary pancreatitis with incomplete penetrance and variable expressivity (20).…”

“…CPA1 mutations and some PRSS1 variants are most likely to exert their pathogenic effect via this pathway (14,30) although misfolding was also observed with a handful of CTRC (1,39) and SPINK1 (4,5,18) variants, and it may also underlie the mechanism of action of the recently described CEL hybrid variant (12). The PRSS1 variants that appeared to cause misfolding (p.K92N, p.D100H, p.R116C, p.S124F, p.C139F, p.C139S, p.G208A) were typically rare and found in sporadic idiopathic cases (14,30, and references therein).…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…Several genetic polymorphisms, including those of alcoholmetabolizing enzymes, are positively associated with an increased occurrence of chronic alcoholic pancreatitis [154][155][156][157][158]. Based on this and in the chronic long-term exposure to EE, we postulate that NAFPD patients carrying these polymorphisms are at increased risk of developing disease progression [159,160] and alcohol-related cancers [61, [160][161][162][163][164].…”