Abstract
Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10−16). The association was strongest in subjects aged ≤10 years (9.7%; OR = 84.0, P = 4.1 × 10−24). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.
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References
Witt, H., Apte, M.V., Keim, V. & Wilson, J.S. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 132, 1557–1573 (2007).
Whitcomb, D.C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat. Genet. 14, 141–145 (1996).
Witt, H., Luck, W. & Becker, M. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 117, 7–10 (1999).
Le Maréchal, C. et al. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat. Genet. 38, 1372–1374 (2006).
Witt, H. et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat. Genet. 25, 213–216 (2000).
Chandak, G.R. et al. Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis. J. Med. Genet. 39, 347–351 (2002).
Rosendahl, J. et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat. Genet. 40, 78–82 (2008).
Masson, E., Chen, J.M., Scotet, V., Le Maréchal, C. & Férec, C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum. Genet. 123, 83–91 (2008).
Witt, H. et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat. Genet. 38, 668–673 (2006).
Whitcomb, D.C. et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat. Genet. 44, 1349–1354 (2012).
Vendrell, J., Querol, E. & Avilés, F.X. Metallocarboxypeptidases and their protein inhibitors. Structure, function and biomedical properties. Biochim. Biophys. Acta 1477, 284–298 (2000).
Szmola, R. et al. Chymotrypsin C is a co-activator of human pancreatic procarboxypeptidases A1 and A2. J. Biol. Chem. 286, 1819–1827 (2011).
Scheele, G., Bartelt, D. & Bieger, W. Characterization of human exocrine pancreatic proteins by two-dimensional isoelectric focusing/sodium dodecyl sulfate gel electrophoresis. Gastroenterology 80, 461–473 (1981).
Rosendahl, J. et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut 62, 582–592 (2013).
Kereszturi, E. et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum. Mutat. 30, 575–582 (2009).
Beer, S. et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut doi:10.1136/gutjnl-2012-303090 (1 September 2012).10.1136/gutjnl-2012-303090
Mock, W.L., Liu, Y. & Stanford, D.J. Arazoformyl peptide surrogates as spectrophotometric kinetic assay substrates for carboxypeptidase A. Anal. Biochem. 239, 218–222 (1996).
Acknowledgements
The authors thank all study participants and the members of the Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) for providing clinical data and blood samples. The authors also thank C. Ruffert (Leipzig), K. Krohn, K. Schön and B. Oelzner (Interdisziplinäres Zentrum für Klinische Forschung (IZKF) core unit DNA technologies, Leipzig), V. Sahin-Tóth (Boston) and K.R. Mani (CCMB, Hyderabad) for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants Wi 2036/2-2 and Wi 2036/2-3 (to H.W.) and RO 3929/1-1 and RO 3939/2-1 (to J.R.), the Else Kröner-Fresenius-Foundation (EKFS) (to H.W.), a grant of the Colora Stiftung gGmbH (to J.R.), US National Institutes of Health (NIH) grants R01DK058088, R01DK082412, R01DK082412-S2 and R01DK095753 (to M.S.-T.), fellowships from the Rosztoczy Foundation (to M. Bence and A. Schnúr), the Bolyai postdoctoral fellowship from the Hungarian Academy of Sciences (to R.S.), INSERM, the Programme Hospitalier de Recherche Clinique (PHRC R 08-04), the French Association des Pancréatites Chroniques Héréditaires and its president N. Meslet, the Czech Ministry of Health conceptual development project of research organization University Hospital Motol in Prague (00064203) and grants CZ.2.16/3.1.00/24022OPPK (to M.M.), the Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, India grant GENESIS (to G.R.C.), a Grant-in-Aid from the Japan Society for the Promotion of Science (#23591008 to A.M.) and the Research Committee of Intractable Pancreatic Diseases provided by the Ministry of Health, Labour and Welfare of Japan (to A.M. and T.S.).
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H.W. and M.S.-T. conceived, designed and directed the study. G.R.C., J.-M.C., J.R., A.M. and H.W. designed, performed and interpreted genetic analyses with substantial contributions from D.B., F.B., M. Braun, S. Bhaskar, C.D., D.L., E.M., S.P., S.S., A.S.-T., K.K., E.N., Y.K., T.S., J.T. and A. Schneider. S. Beer, M. Bence, R.S., A. Szabó, A. Schnúr and M.S.-T. carried out functional characterization of CPA1 variants. H.W., M.S.-T. and S. Beer wrote the manuscript with substantial contributions from G.R.C., J.-M.C., J.R. and A.M. O.L. provided oligonucleotides. All other coauthors recruited study 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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Witt, H., Beer, S., Rosendahl, J. et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 45, 1216–1220 (2013). https://doi.org/10.1038/ng.2730
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DOI: https://doi.org/10.1038/ng.2730
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