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Chronic pancreatitis is a persistent inflammatory disease of the pancreas. The digestive protease trypsin plays a fundamental role in the pathogenesis. Here we analyzed the gene encoding the trypsindegrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group and were present in 30/901 (3.3%) affected individuals but only in 21/2,804 (0.7%) controls (OR=4.6; CI=2.6−8.0; P=1.3×10 −7 ). A replication study identified these two variants in 10/348 (2.9%) individuals with alcoholic chronic pancreatitis but only in 3/432 (0.7%) subjects with alcoholic liver disease (OR=4.2; CI=1.2−15.5; P=0.02). CTRC variants were also found in 10/71 (14.1%) Indian subjects with tropical pancreatitis but only in 1/84 (1.2%) control (OR=13.6; CI=1.7 −109.2; P=0.0028). Functional analysis of the CTRC variants revealed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.Chronic pancreatitis is a continuing inflammatory disorder characterized by permanent destruction of the pancreatic parenchyma leading to maldigestion and diabetes mellitus due to exocrine and endocrine insufficiency. Penetrating insight into the pathomechanism came from relatively recent studies investigating the genes encoding cationic trypsinogen (PRSS1; OMIM 276000), anionic trypsinogen (PRSS2; OMIM 601564), and the pancreatic secretory trypsin inhibitor (SPINK1; OMIM 167790). Gain-of-function variants in PRSS1 have been linked to autosomal dominant hereditary pancreatitis and subsequently also to idiopathic chronic pancreatitis 1-4 . Recently, triplication of the PRSS1 locus has been observed in a subset of families with hereditary pancreatitis 5 . In vitro biochemical studies revealed that the majority of disease predisposing PRSS1 variants increase autocatalytic conversion of trypsinogen to active trypsin and probably promote premature intrapancreatic trypsin activation in vivo 6,7 . Consistent with the central pathophysiological role of trypsin, p.N34S and other loss-offunction alterations in the trypsin inhibitor SPINK1 predispose to idiopathic, tropical, and alcoholic chronic pancreatitis 8-15 . In contrast to pathogenic PRSS1 and SPINK1 variations, the p.G191R PRSS2 variant affords protection against chronic pancreatitis due to rapid autodegradation 16 . Taken together, genetic and biochemical evidence defines a pathological pathway in which a sustained imbalance between intrapancreatic trypsinogen activation and trypsin inactivation results in the development of chronic pancreatitis ( Supplementary Fig. 1).Because trypsin degradation serves as a protective mechanism against pancreatitis, we hypothesized that loss of function in trypsin degrading enzymes increases the risk for pancreatitis. We recently demonstrated that chymotrypsin C (CTRC) degrades all human tryps...

To characterize at the molecular level the pancreatic emergency program set up by the pancreatic cells in response to pancreatitis, we have developed a strategy in which the phenotype of the pancreatitis affected pancreas is established by characterization of a large number of its transcripts. Herein, we describe the cloning, sequence, and expression of a new gene, named p8, which is strongly activated in pancreatic acinar cells during the acute phase of pancreatitis, in developing pancreas and during pancreatic regeneration. In acinar cells, p8 mRNA is expressed rapidly and specifically in response to cellular pancreatitis-induced injury; its induction occurred almost similarly in edematous and necrohemorrhagic pancreatitis, indicating that p8 mRNA is maximally activated even in response to a mild pancreatic injury. Furthermore, in vitro studies suggest that p8 mRNA is induced in pancreatic and non-pancreatic cells in response to some apoptotic stimuli. p8 acts as a promoter of cellular growth factor when its cDNA is transfected into COS-7 and AR4-2J cells. Although we failed to identify p8-related sequences, analysis of its primary and secondary structure suggests that p8 is a basic helix-turn-helix-containing gene with slight homology to several homeotic genes and sufficient signal to be targeted to the nucleus. We therefore propose p8 as a putative transcriptional factor which can regulate pancreatic growth.