Variants in CPA1 are strongly associated with early onset chronic pancreatitis
Open accessAbstract
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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PRSS1, CPA1 and CTRC are associated with significantly increased risk of developing pancreatitis.
“The pancreatitis susceptibility genes, PRSS1, CPA1 and CTRC, are associated with significantly increased risk of developing pancreatitis.”
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- Authors
- Witt, H., Beer, S., Rosendahl, J., Chen, J.-M., Chandak, G. R., Masamune, A., Bence, M., Szmola, R., Oracz, G., Macek, M., Bhatia, E., Steigenberger, S., Lasher, D., Bühler, F., Delaporte, C., Tebbing, J., Ludwig, M., Pilsak, C., Saum, K., Bugert, P., Masson, E., Paliwal, S., Bhaskar, S., Sobczynska-Tomaszewska, A., Bak, D., Balascak, I., Choudhuri, G., Reddy, D. N., Rao, G. V., Thomas, V., Kume, K., Nakano, E., Kakuta, Y., Shimosegawa, T., Durko, L., Szabó, A., Schnúr, A., Hegyi, P., Rakonczay, Z., Pfützer, R., Schneider, A., Groneberg, D. A., Braun, M., Schmidt, H., Witt, U., Friess, H., Algül, H., Landt, O., Schuelke, M., Krüger, R., Wiedenmann, B., Schmidt, F., Zimmer, K.-P., Kovacs, P., Stumvoll, M., Blüher, M., Müller, T., Janecke, A., Teich, N., Grützmann, R., Schulz, H.-U., Mössner, J., Keim, V., Löhr, M., Férec, C., & Sahin-Tóth, M.
- Affiliations
- TUM Klinikum (DE)
- Boston University (US)
- Leipzig University (DE)
- Inserm (FR)
- Centre for Cellular and Molecular Biology (IN)
- Tohoku University (JP)
- Semmelweis University (HU)
- Children's Memorial Health Institute (PL)
- Sanjay Gandhi Post Graduate Institute of Medical Sciences (IN)
- Else Kröner Fresenius Zentrum für Ernährungsmedizin (DE)
- Heidelberg University (DE)
- Asian Institute of Gastroenterology (IN)
- Government Medical College (IN)
- University of Szeged (HU)
- Goethe University Frankfurt (DE)
- University Hospital Münster (DE)
- Technical University of Munich (DE)
- TIB Molbiol (Germany) (DE)
- Stiftung Charité (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Justus-Liebig-Universität Gießen (DE)
- IFB Adiposity Diseases (DE)
- Innsbruck Medical University (AT)
- University Hospital Carl Gustav Carus (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Karolinska University Hospital (SE)
- Corresponding author
- Witt, Heiko
- ORCID
- Witt, Heiko
- Beer, Sebastian
- Rosendahl, Jonas
- Chen, Jian-Min
- Chandak, Giriraj Ratan
- Masamune, Atsushi
- Bence, Melinda
- Szmola, Richárd
- Oracz, Grzegorz
- Bhatia, Eesh
- Bugert, Peter
- Masson, Emmanuelle
- Paliwal, Sumit
- Thomas, Varghese
- Kume, Kiyoshi
- Nakano, Eriko
- Kakuta, Yoichi
- Shimosegawa, Tooru
- Szabó, András
- Schnúr, Andrea
- Hegyi, Péter
- Rakonczay, Zoltán
- Groneberg, David Alexander
- Braun, Markus
- Schmidt, Hartmut
- Algül, Hana
- Landt, Olfert
- Schuelke, Markus
- Krüger, Renate
- Wiedenmann, Bertram
- Kovacs, Peter
- Blüher, Matthias
- Müller, Thomas
- Janecke, Andreas
- Teich, Niels
- Grützmann, Robert
- Löhr, Matthias
- Férec, Claude
- Venue
- Nature Genetics
- Published
- 2013-08-18
- Volume
- 45
- Issue
- 10
- Pages
- 1216-1220
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3909499
- OpenAlex
- W2003115684
- Cited by
- 305
- References
- 17
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 24 · 2023: 16 · 2022: 23 · 2021: 25 · 2020: 25 · 2019: 28 · 2018: 31 · 2017: 34 · 2016: 25 · 2015: 26 · 2014: 22 · 2013: 2
- FWCI
- 24.99
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (23591008)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082412-S2, R01DK058088, R01DK082412, R01DK095753)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- chronic pancreatitis, CPA1, loss-of-function mutations, genetic susceptibility, endoplasmic reticulum stress, protein misfolding, trypsin activity
- MeSH terms
- Adolescent, Adult, Child, Humans, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Carboxypeptidases A, Pancreatitis, Chronic, Young Adult
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