Variants in CPA1 are strongly associated with early onset chronic pancreatitis.

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.

• Authors: Heiko Witt, Sebastian Beer, Jonas Rosendahl, Jian-Min Chen, Giriraj Ratan Chandak, Atsushi Masamune, Melinda Bence, Richárd Szmola, Grzegorz Oracz, Milan Macek Jr, Eesh Bhatia, Sandra Steigenberger, Denise Lasher, Florence Bühler, Catherine Delaporte, Johanna Tebbing, Maren Ludwig, Claudia Pilsak, Karolin Saum, Peter Bugert, Emmanuelle Masson, Sumit Paliwal, Seema Bhaskar, Agnieszka Sobczynska-Tomaszewska, Daniel Bak, Ivan Balascak, Gourdas Choudhuri, D Nageshwar Reddy, G Venkat Rao, Varghese Thomas, Kiyoshi Kume, Eriko Nakano, Yoichi Kakuta, Tooru Shimosegawa, Lukasz Durko, András Szabó, Andrea Schnúr, Péter Hegyi, Zoltán Rakonczay Jr, Roland Pfützer, Alexander Schneider, David Alexander Groneberg, Markus Braun, Hartmut Schmidt, Ulrike Witt, Helmut Friess, Hana Algül, Olfert Landt, Markus Schuelke, Renate Krüger, Bertram Wiedenmann, Frank Schmidt, Klaus-Peter Zimmer, Peter Kovacs, Michael Stumvoll, Matthias Blüher, Thomas Müller, Andreas Janecke, Niels Teich, Robert Grützmann, Hans-Ulrich Schulz, Joachim Mössner, Volker Keim, Matthias Löhr, Claude Férec, Miklós Sahin-Tóth
• Journal: Nature genetics (Nat Genet) Vol. 45 Issue 10 Pg. 1216-20 (Oct 2013) ISSN: 1546-1718 [Electronic] United States
• PMID: 23955596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxypeptidases A

Topics

• Adolescent
• Adult
• Age of Onset
• Carboxypeptidases A (genetics)
• Case-Control Studies
• Child
• Genetic Predisposition to Disease
• Humans
• Pancreatitis, Chronic (genetics)
• Young Adult