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Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis

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 × 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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Figure 1: Effects of pancreatitis-associated CTRC variants on the secretion of chymotrypsinogen C.

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Acknowledgements

We thank the individuals who have participated in this study. We also thank A. Schulzki, M. Braun and V. Sahin-Tóth for excellent technical assistance. This work was supported by US National Institutes of Health grant DK058088 (to M.S.-T.), a scholarship from the Rosztoczy Foundation (to B.O.), by the Medical Faculty of the University of Leipzig formel.1 (to J.R.), and the Deutsche Forschungsgemeinschaft (DFG) grant Te 352/2-1 (to N.T.) and grants Wi 2036/2-1 and Wi 2036/2-2 (to H.W.).

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Contributions

M.S.-T., N.T. and H.W. conceived, designed and directed the study. J.R. and H.W. designed, performed and interpreted genetic analyses. R.S., M.S.-T. and B.O. carried out functional characterization of CTRC variants. M.S.-T. wrote the manuscript with significant contributions from R.S., H.W. and J.R. O.L. provided oligonucleotides. N.T., J.R., H.W. and all other coauthors recruited patients and control subjects, collected clinical data and provided genomic DNA samples. All authors approved the final manuscript and contributed critical revisions to its intellectual content.

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Correspondence to Miklós Sahin-Tóth.

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Supplementary Figures 1 and 2, Supplementary Tables 1 and 2, Supplementary Methods (PDF 86 kb)

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Rosendahl, J., Witt, H., Szmola, R. et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 40, 78–82 (2008). https://doi.org/10.1038/ng.2007.44

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