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

Jonas Rosendahl, Heiko Witt, R. Szmola, Eesh Bhatia, Béla Ózsvári, Olfert Landt, Hans Ulrich Schulz, Thomas M. Gress, Roland Pfützer, Matthias Löhr, Peter Kovacs, Matthias Blüher, Michael Stumvoll, Gourdas Choudhuri, P. Hegyi, René H M Te Morsche, Joost P H Drenth, Kaspar Truninger, Milan Macek, Gero Puhl & 14 others Ulrike Witt, Hartmut Schmidt, Carsten Büning, Johann Ockenga, Andreas Kage, David Alexander Groneberg, Renate Nickel, Thomas Berg, Bertram Wiedenmann, Hans Bödeker, Volker Keim, Joachim Mössner, Niels Teich, Miklós Sahin-Tóth

Research output: Contribution to journalArticle

218 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)78-82
Number of pages5
JournalNature Genetics
Volume40
Issue number1
DOIs
Publication statusPublished - Jan 2008

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Chronic Pancreatitis
Pancreatitis
Trypsin
Odds Ratio
Confidence Intervals
Alcoholic Pancreatitis
Alcoholic Liver Diseases
Genes
Pancreas
Peptide Hydrolases
chymotrypsin C
Enzymes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. / Rosendahl, Jonas; Witt, Heiko; Szmola, R.; Bhatia, Eesh; Ózsvári, Béla; Landt, Olfert; Schulz, Hans Ulrich; Gress, Thomas M.; Pfützer, Roland; Löhr, Matthias; Kovacs, Peter; Blüher, Matthias; Stumvoll, Michael; Choudhuri, Gourdas; Hegyi, P.; 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, Vol. 40, No. 1, 01.2008, p. 78-82.

Research output: Contribution to journalArticle

Rosendahl, J, Witt, H, Szmola, R, Bhatia, E, Ózsvári, B, Landt, O, Schulz, HU, Gress, TM, Pfützer, R, Löhr, M, Kovacs, P, Blüher, M, Stumvoll, M, Choudhuri, G, Hegyi, P, Te Morsche, RHM, Drenth, JPH, Truninger, K, Macek, M, Puhl, G, Witt, U, Schmidt, H, Büning, C, Ockenga, J, Kage, A, Groneberg, DA, Nickel, R, Berg, T, Wiedenmann, B, Bödeker, H, Keim, V, Mössner, J, Teich, N & Sahin-Tóth, M 2008, 'Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis', Nature Genetics, vol. 40, no. 1, pp. 78-82. https://doi.org/10.1038/ng.2007.44
Rosendahl, Jonas ; Witt, Heiko ; Szmola, R. ; Bhatia, Eesh ; Ózsvári, Béla ; Landt, Olfert ; Schulz, Hans Ulrich ; Gress, Thomas M. ; Pfützer, Roland ; Löhr, Matthias ; Kovacs, Peter ; Blüher, Matthias ; Stumvoll, Michael ; Choudhuri, Gourdas ; Hegyi, P. ; 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. / Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. In: Nature Genetics. 2008 ; Vol. 40, No. 1. pp. 78-82.
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AU - Ózsvári, Béla

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AU - Pfützer, Roland

AU - Löhr, Matthias

AU - Kovacs, Peter

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AU - Groneberg, David Alexander

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AU - Wiedenmann, Bertram

AU - Bödeker, Hans

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