Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.
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.
Rosendahl
Jonas
J
Department of Gastroenterology and Hepatology, University of Leipzig, Philipp-Rosenthal-Strasse 27, 04103 Leipzig, Germany.
Witt
Heiko
H
Szmola
Richárd
R
Bhatia
Eesh
E
Ozsvári
Béla
B
Landt
Olfert
O
Schulz
Hans-Ulrich
HU
Gress
Thomas M
TM
Pfützer
Roland
R
Löhr
Matthias
M
Kovacs
Peter
P
Blüher
Matthias
M
Stumvoll
Michael
M
Choudhuri
Gourdas
G
Hegyi
Péter
P
te Morsche
René H M
RH
Drenth
Joost P H
JP
Truninger
Kaspar
K
Macek
Milan
M
Puhl
Gero
G
Witt
Ulrike
U
Schmidt
Hartmut
H
Büning
Carsten
C
Ockenga
Johann
J
Kage
Andreas
A
Groneberg
David Alexander
DA
Nickel
Renate
R
Berg
Thomas
T
Wiedenmann
Bertram
B
Bödeker
Hans
H
Keim
Volker
V
Mössner
Joachim
J
Teich
Niels
N
Sahin-Tóth
Miklós
M
D002460:Cell Line; D002918:Chymotrypsin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005858:Germany; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019512:Pancreatitis, Alcoholic / Q000235:genetics; D050500:Pancreatitis, Chronic / Q000235:genetics*
D002918:Chymotrypsin; C117569:chymotrypsin C