Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis by Rosendahl Jonas, Witt Heiko, Szmola Richárd, Bhatia Eesh, Ozsvári Béla, Landt Olfert, Schulz Hans-Ulrich, Gress Thomas M, Pfützer Roland, Löhr Matthias, Kovacs Peter, Blüher Matthias, Stumvoll Michael, Choudhuri Gourdas, Hegyi Péter, te Morsche René H M, Drenth Joost P H, Truninger Kaspar, Macek Milan, Puhl Gero, Witt Ulrike, Schmidt Hartmut, Büning Carsten, Ockenga Johann, Kage Andreas, Groneberg David Alexander, Nickel Renate, Berg Thomas, Wiedenmann Bertram, Bödeker Hans, Keim Volker, Mössner Joachim, Teich Niels, Sahin-Tóth Miklós in Nature genetics (2008). PubMed

Abstract

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 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 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed 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.

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