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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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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