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

Jonas Rosendahl; Heiko Witt; Richárd 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; Péter Hegyi; René H.M. Te Morsche; Joost P.H. Drenth; Kaspar Truninger; Milan Macek; Gero Puhl; 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

doi:10.1038/ng.2007.44

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

Jonas Rosendahl, Heiko Witt, Richárd 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, Péter Hegyi, René H.M. Te Morsche, Joost P.H. Drenth, Kaspar Truninger, Milan Macek, Gero PuhlUlrike 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

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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 language	English
Pages (from-to)	78-82
Number of pages	5
Journal	Nature Genetics
Volume	40
Issue number	1
DOIs	https://doi.org/10.1038/ng.2007.44
State	Published - Jan 2008
Externally published	Yes

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Rosendahl, J., Witt, H., Szmola, R., Bhatia, E., Ózsvári, B., Landt, O., Schulz, H. U., Gress, T. M., Pfützer, R., Löhr, M., Kovacs, P., Blüher, M., Stumvoll, M., Choudhuri, G., Hegyi, P., Te Morsche, R. H. M., Drenth, J. P. H., Truninger, K., Macek, M., ... Sahin-Tóth, M. (2008). Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nature Genetics, 40(1), 78-82. https://doi.org/10.1038/ng.2007.44

@article{5317870c849047759a1199166186ac0c,

title = "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.",

author = "Jonas Rosendahl and Heiko Witt and Rich{\'a}rd Szmola and Eesh Bhatia and B{\'e}la {\'O}zsv{\'a}ri and Olfert Landt and Schulz, {Hans Ulrich} and Gress, {Thomas M.} and Roland Pf{\"u}tzer and Matthias L{\"o}hr and Peter Kovacs and Matthias Bl{\"u}her and Michael Stumvoll and Gourdas Choudhuri and P{\'e}ter Hegyi and {Te Morsche}, {Ren{\'e} H.M.} and Drenth, {Joost P.H.} and Kaspar Truninger and Milan Macek and Gero Puhl and Ulrike Witt and Hartmut Schmidt and Carsten B{\"u}ning and Johann Ockenga and Andreas Kage and Groneberg, {David Alexander} and Renate Nickel and Thomas Berg and Bertram Wiedenmann and Hans B{\"o}deker and Volker Keim and Joachim M{\"o}ssner and Niels Teich and Mikl{\'o}s Sahin-T{\'o}th",

note = "Funding Information: We thank the individuals who have participated in this study. We also thank A. Schulzki, M. Braun and V. Sahin-T{\'o}th 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.).",

year = "2008",

month = jan,

doi = "10.1038/ng.2007.44",

language = "English",

volume = "40",

pages = "78--82",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

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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

TY - JOUR

T1 - Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis

AU - Rosendahl, Jonas

AU - Witt, Heiko

AU - Szmola, Richárd

AU - Bhatia, Eesh

AU - Ózsvári, Béla

AU - Landt, Olfert

AU - Schulz, Hans Ulrich

AU - Gress, Thomas M.

AU - Pfützer, Roland

AU - Löhr, Matthias

AU - Kovacs, Peter

AU - Blüher, Matthias

AU - Stumvoll, Michael

AU - Choudhuri, Gourdas

AU - Hegyi, Péter

AU - Te Morsche, René H.M.

AU - Drenth, Joost P.H.

AU - Truninger, Kaspar

AU - Macek, Milan

AU - Puhl, Gero

AU - Witt, Ulrike

AU - Schmidt, Hartmut

AU - Büning, Carsten

AU - Ockenga, Johann

AU - Kage, Andreas

AU - Groneberg, David Alexander

AU - Nickel, Renate

AU - Berg, Thomas

AU - Wiedenmann, Bertram

AU - Bödeker, Hans

AU - Keim, Volker

AU - Mössner, Joachim

AU - Teich, Niels

AU - Sahin-Tóth, Miklós

N1 - Funding Information: 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.).

PY - 2008/1

Y1 - 2008/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=37549072225&partnerID=8YFLogxK

U2 - 10.1038/ng.2007.44

DO - 10.1038/ng.2007.44

M3 - Article

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AN - SCOPUS:37549072225

SN - 1061-4036

VL - 40

SP - 78

EP - 82

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

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