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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.

SUBMITTER: Witt H 

PROVIDER: S-EPMC3909499 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Witt Heiko H   Beer Sebastian S   Rosendahl Jonas J   Chen Jian-Min JM   Chandak Giriraj Ratan GR   Masamune Atsushi A   Bence Melinda M   Szmola Richárd R   Oracz Grzegorz G   Macek Milan M   Bhatia Eesh E   Steigenberger Sandra S   Lasher Denise D   Bühler Florence F   Delaporte Catherine C   Tebbing Johanna J   Ludwig Maren M   Pilsak Claudia C   Saum Karolin K   Bugert Peter P   Masson Emmanuelle E   Paliwal Sumit S   Bhaskar Seema S   Sobczynska-Tomaszewska Agnieszka A   Bak Daniel D   Balascak Ivan I   Choudhuri Gourdas G   Nageshwar Reddy D D   Rao G Venkat GV   Thomas Varghese V   Kume Kiyoshi K   Nakano Eriko E   Kakuta Yoichi Y   Shimosegawa Tooru T   Durko Lukasz L   Szabó András A   Schnúr Andrea A   Hegyi Péter P   Rakonczay Zoltán Z   Pfützer Roland R   Schneider Alexander A   Groneberg David Alexander DA   Braun Markus M   Schmidt Hartmut H   Witt Ulrike U   Friess Helmut H   Algül Hana H   Landt Olfert O   Schuelke Markus M   Krüger Renate R   Wiedenmann Bertram B   Schmidt Frank F   Zimmer Klaus-Peter KP   Kovacs Peter P   Stumvoll Michael M   Blüher Matthias M   Müller Thomas T   Janecke Andreas A   Teich Niels N   Grützmann Robert R   Schulz Hans-Ulrich HU   Mössner Joachim J   Keim Volker V   Löhr Matthias M   Férec Claude C   Sahin-Tóth Miklós M  

Nature genetics 20130818 10


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 replicatio  ...[more]

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