Variants in CPA1 are strongly associated with early onset chronic pancreatitis

Heiko Witt; Sebastian Beer; Jonas Rosendahl; Jian Min Chen; Giriraj Ratan Chandak; Atsushi Masamune; Melinda Bence; Richárd Szmola; Grzegorz Oracz; Milan Macek; 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; 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

doi:10.1038/ng.2730

Variants in CPA1 are strongly associated with early onset chronic pancreatitis

Heiko Witt, Sebastian Beer, Jonas Rosendahl, Jian Min Chen, Giriraj Ratan Chandak, Atsushi Masamune, Melinda Bence, Richárd Szmola, Grzegorz Oracz, Milan Macek, Eesh Bhatia, Sandra Steigenberger, Denise Lasher, Florence Bühler, Catherine Delaporte, Johanna Tebbing, Maren Ludwig, Claudia Pilsak, Karolin Saum, Peter BugertEmmanuelle 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, 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

Medicine and Health

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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. unctionally 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 X 10-16). The association was strongest in subjects aged =10 years (9.7%; OR = 84.0, P = 4.1 X 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.

Original language	English
Pages (from-to)	1216-1220
Number of pages	5
Journal	Nature Genetics
Volume	45
Issue number	10
DOIs	https://doi.org/10.1038/ng.2730
State	Published - Oct 2013

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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., ... Sahin-Tóth, M. (2013). Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nature Genetics, 45(10), 1216-1220. https://doi.org/10.1038/ng.2730

@article{c8fc1d0714cd46a691a74b8588dbc883,

title = "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. unctionally 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 X 10-16). The association was strongest in subjects aged =10 years (9.7%; OR = 84.0, P = 4.1 X 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.",

author = "Heiko Witt and Sebastian Beer and Jonas Rosendahl and Chen, {Jian Min} and Chandak, {Giriraj Ratan} and Atsushi Masamune and Melinda Bence and Rich{\'a}rd Szmola and Grzegorz Oracz and Milan Macek and Eesh Bhatia and Sandra Steigenberger and Denise Lasher and Florence B{\"u}hler and Catherine Delaporte and Johanna Tebbing and Maren Ludwig and Claudia Pilsak and Karolin Saum and Peter Bugert and Emmanuelle Masson and Sumit Paliwal and Seema Bhaskar and Agnieszka Sobczynska-Tomaszewska and Daniel Bak and Ivan Balascak and Gourdas Choudhuri and Reddy, {D. Nageshwar} and Rao, {G. Venkat} and Varghese Thomas and Kiyoshi Kume and Eriko Nakano and Yoichi Kakuta and Tooru Shimosegawa and Lukasz Durko and Andr{\'a}s Szab{\'o} and Andrea Schn{\'u}r and P{\'e}ter Hegyi and Zolt{\'a}n Rakonczay and Roland Pf{\"u}tzer and Alexander Schneider and Groneberg, {David Alexander} and Markus Braun and Hartmut Schmidt and Ulrike Witt and Helmut Friess and Hana Alg{\"u}l and Olfert Landt and Markus Schuelke and Renate Kr{\"u}ger and Bertram Wiedenmann and Frank Schmidt and Zimmer, {Klaus Peter} and Peter Kovacs and Michael Stumvoll and Matthias Bl{\"u}her and Thomas M{\"u}ller and Andreas Janecke and Niels Teich and Robert Gr{\"u}tzmann and Schulz, {Hans Ulrich} and Joachim M{\"o}ssner and Volker Keim and Matthias L{\"o}hr and Claude F{\'e}rec and Mikl{\'o}s Sahin-T{\'o}th",

note = "Funding Information: The authors thank all study participants and the members of the Gesellschaft f{\"u}r P{\"a}diatrische Gastroenterologie und Ern{\"a}hrung (GPGE) for providing clinical data and blood samples. The authors also thank C. Ruffert (Leipzig), K. Krohn, K. Sch{\"o}n and B. Oelzner (Interdisziplin{\"a}res Zentrum f{\"u}r Klinische Forschung (IZKF) core unit DNA technologies, Leipzig), V. Sahin-T{\'o}th (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 Kr{\"o}ner-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. Schn{\'u}r), 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 Pancr{\'e}atites Chroniques H{\'e}r{\'e}ditaires 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.). Funding Information: 1Else Kr{\"o}ner-Fresenius-Zentrum f{\"u}r Ern{\"a}hrungsmedizin (EKFZ), Technische Universit{\"a}t M{\"u}nchen (TUM), Freising, Germany. 2Zentralinstitut f{\"u}r Ern{\"a}hrungs-und Lebensmittelforschung (ZIEL), TUM, Freising, Germany. 3Department of Pediatrics, Klinikum Rechts der Isar (MRI), TUM, Munich, Germany. 4Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA. 5Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany. 6Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), U1078, Etablissement Fran{\c c}ais du Sang (EFS)–Bretagne, Brest, France. 7Facult{\'e} de M{\'e}decine et des Sciences de la Sant{\'e}, Universit{\'e} de Bretagne Occidentale, Brest, France. 8Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Hyderabad, India. 9Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 102nd Department of Medicine, Semmelweis University, Budapest, Hungary. 11Department of Gastroenterology, Hepatology and Immunology, The Children{\textquoteright}s Memorial Health Institute, Warsaw, Poland. 12Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine of Charles University Prague, Prague, Czech Republic. 13Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. 14Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 15MedGen Health Care Centre, Warsaw, Poland. 16Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 17Clinic of Obstetrics and Gynecology, Department of Neonatology, University Hospital Motol and 2nd Medical School, Charles University Prague, Prague, Czech Republic. 18Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. 19Asian Institute of Gastroenterology, Hyderabad, India. 20Department of Gastroenterology, Medical College Hospital, Calicut, India. 21Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. 221st Department of Medicine, University of Szeged, Szeged, Hungary. 23Department of Internal Medicine, Klinikum D{\"o}beln, D{\"o}beln, Germany. 24Department of Medicine II, Universit{\"a}tsmedizin Mannheim, Ruprecht-Karls-Universit{\"a}t Heidelberg, Mannheim, Germany. 25Institute for Occupational Medicine, Goethe-Universit{\"a}t Frankfurt, Frankfurt, Germany. 26Department for Transplant Medicine, University Hospital M{\"u}nster, Albert-Schweitzer-Campus 1, M{\"u}nster, Germany. 27Department of Surgery, TUM, Munich, Germany. 28Department of Gastroenterology, TUM, Munich, Germany. 29TIB MOLBIOL, Berlin, Germany. 30Department of Neuropediatrics, Charit{\'e}, Campus Virchow-Klinikum, Berlin, Germany. 31NeuroCure Clinical Research Center, Charit{\'e}, Campus Virchow-Klinikum, Berlin, Germany. 32Department of Pediatrics, Division of Pediatric Pulmonology, Charit{\'e}, Campus Virchow-Klinikum, Berlin, Germany. 33Department of Internal Medicine, Division of Hepatology and Gastroenterology, Charit{\'e}, Campus Virchow-Klinikum, Berlin, Germany. 34Department of Pediatrics, University of Halle-Wittenberg, Halle (Saale), Germany. 35Department of Pediatrics, Justus-Liebig-Universit{\"a}t, Gie{\ss}en, Germany. 36Department for Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany. 37Integriertes Forschungs-und Behandlungszentrum (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. 38Universit{\"a}tsklinik f{\"u}r P{\"a}diatrie I, Department f{\"u}r Kinder-und Jugendheilkunde, Medizinische Universit{\"a}t Innsbruck, Innsbruck, Austria. 39Sektion f{\"u}r Humangenetik, Medizinische Universit{\"a}t Innsbruck, Innsbruck, Austria. 40Practice for Digestive and Metabolic Diseases, Leipzig, Germany. 41Department of Surgery, Universit{\"a}tsklinikum Dresden, Dresden, Germany. 42Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 43Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 44These authors contributed equally to this work. Correspondence should be addressed to H.W. ([email protected]) or M.S.-T. ([email protected]).",

year = "2013",

month = oct,

doi = "10.1038/ng.2730",

language = "English",

volume = "45",

pages = "1216--1220",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Witt, H, Beer, S, Rosendahl, J, Chen, JM, Chandak, GR, 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, DN, Rao, GV, 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, DA, Braun, M, Schmidt, H, Witt, U, Friess, H , Algül, H, Landt, O, Schuelke, M, Krüger, R, Wiedenmann, B, Schmidt, F, Zimmer, KP, Kovacs, P, Stumvoll, M, Blüher, M, Müller, T, Janecke, A, Teich, N, Grützmann, R, Schulz, HU, Mössner, J, Keim, V, Löhr, M, Férec, C & Sahin-Tóth, M 2013, 'Variants in CPA1 are strongly associated with early onset chronic pancreatitis', Nature Genetics, vol. 45, no. 10, pp. 1216-1220. https://doi.org/10.1038/ng.2730

TY - JOUR

T1 - Variants in CPA1 are strongly associated with early onset chronic pancreatitis

AU - Witt, Heiko

AU - Beer, Sebastian

AU - Rosendahl, Jonas

AU - Chen, Jian Min

AU - Chandak, Giriraj Ratan

AU - Masamune, Atsushi

AU - Bence, Melinda

AU - Szmola, Richárd

AU - Oracz, Grzegorz

AU - Macek, Milan

AU - Bhatia, Eesh

AU - Steigenberger, Sandra

AU - Lasher, Denise

AU - Bühler, Florence

AU - Delaporte, Catherine

AU - Tebbing, Johanna

AU - Ludwig, Maren

AU - Pilsak, Claudia

AU - Saum, Karolin

AU - Bugert, Peter

AU - Masson, Emmanuelle

AU - Paliwal, Sumit

AU - Bhaskar, Seema

AU - Sobczynska-Tomaszewska, Agnieszka

AU - Bak, Daniel

AU - Balascak, Ivan

AU - Choudhuri, Gourdas

AU - Reddy, D. Nageshwar

AU - Rao, G. Venkat

AU - Thomas, Varghese

AU - Kume, Kiyoshi

AU - Nakano, Eriko

AU - Kakuta, Yoichi

AU - Shimosegawa, Tooru

AU - Durko, Lukasz

AU - Szabó, András

AU - Schnúr, Andrea

AU - Hegyi, Péter

AU - Rakonczay, Zoltán

AU - Pfützer, Roland

AU - Schneider, Alexander

AU - Groneberg, David Alexander

AU - Braun, Markus

AU - Schmidt, Hartmut

AU - Witt, Ulrike

AU - Friess, Helmut

AU - Algül, Hana

AU - Landt, Olfert

AU - Schuelke, Markus

AU - Krüger, Renate

AU - Wiedenmann, Bertram

AU - Schmidt, Frank

AU - Zimmer, Klaus Peter

AU - Kovacs, Peter

AU - Stumvoll, Michael

AU - Blüher, Matthias

AU - Müller, Thomas

AU - Janecke, Andreas

AU - Teich, Niels

AU - Grützmann, Robert

AU - Schulz, Hans Ulrich

AU - Mössner, Joachim

AU - Keim, Volker

AU - Löhr, Matthias

AU - Férec, Claude

AU - Sahin-Tóth, Miklós

N1 - Funding Information: 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.). Funding Information: 1Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Technische Universität München (TUM), Freising, Germany. 2Zentralinstitut für Ernährungs-und Lebensmittelforschung (ZIEL), TUM, Freising, Germany. 3Department of Pediatrics, Klinikum Rechts der Isar (MRI), TUM, Munich, Germany. 4Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA. 5Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany. 6Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Etablissement Français du Sang (EFS)–Bretagne, Brest, France. 7Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, Brest, France. 8Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Hyderabad, India. 9Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. 102nd Department of Medicine, Semmelweis University, Budapest, Hungary. 11Department of Gastroenterology, Hepatology and Immunology, The Children’s Memorial Health Institute, Warsaw, Poland. 12Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine of Charles University Prague, Prague, Czech Republic. 13Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. 14Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 15MedGen Health Care Centre, Warsaw, Poland. 16Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. 17Clinic of Obstetrics and Gynecology, Department of Neonatology, University Hospital Motol and 2nd Medical School, Charles University Prague, Prague, Czech Republic. 18Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. 19Asian Institute of Gastroenterology, Hyderabad, India. 20Department of Gastroenterology, Medical College Hospital, Calicut, India. 21Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. 221st Department of Medicine, University of Szeged, Szeged, Hungary. 23Department of Internal Medicine, Klinikum Döbeln, Döbeln, Germany. 24Department of Medicine II, Universitätsmedizin Mannheim, Ruprecht-Karls-Universität Heidelberg, Mannheim, Germany. 25Institute for Occupational Medicine, Goethe-Universität Frankfurt, Frankfurt, Germany. 26Department for Transplant Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Münster, Germany. 27Department of Surgery, TUM, Munich, Germany. 28Department of Gastroenterology, TUM, Munich, Germany. 29TIB MOLBIOL, Berlin, Germany. 30Department of Neuropediatrics, Charité, Campus Virchow-Klinikum, Berlin, Germany. 31NeuroCure Clinical Research Center, Charité, Campus Virchow-Klinikum, Berlin, Germany. 32Department of Pediatrics, Division of Pediatric Pulmonology, Charité, Campus Virchow-Klinikum, Berlin, Germany. 33Department of Internal Medicine, Division of Hepatology and Gastroenterology, Charité, Campus Virchow-Klinikum, Berlin, Germany. 34Department of Pediatrics, University of Halle-Wittenberg, Halle (Saale), Germany. 35Department of Pediatrics, Justus-Liebig-Universität, Gießen, Germany. 36Department for Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany. 37Integriertes Forschungs-und Behandlungszentrum (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. 38Universitätsklinik für Pädiatrie I, Department für Kinder-und Jugendheilkunde, Medizinische Universität Innsbruck, Innsbruck, Austria. 39Sektion für Humangenetik, Medizinische Universität Innsbruck, Innsbruck, Austria. 40Practice for Digestive and Metabolic Diseases, Leipzig, Germany. 41Department of Surgery, Universitätsklinikum Dresden, Dresden, Germany. 42Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 43Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 44These authors contributed equally to this work. Correspondence should be addressed to H.W. ([email protected]) or M.S.-T. ([email protected]).

PY - 2013/10

Y1 - 2013/10

N2 - 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. unctionally 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 X 10-16). The association was strongest in subjects aged =10 years (9.7%; OR = 84.0, P = 4.1 X 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.

AB - 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. unctionally 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 X 10-16). The association was strongest in subjects aged =10 years (9.7%; OR = 84.0, P = 4.1 X 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.

UR - http://www.scopus.com/inward/record.url?scp=84885019350&partnerID=8YFLogxK

U2 - 10.1038/ng.2730

DO - 10.1038/ng.2730

M3 - Article

C2 - 23955596

AN - SCOPUS:84885019350

SN - 1061-4036

VL - 45

SP - 1216

EP - 1220

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Variants in CPA1 are strongly associated with early onset chronic pancreatitis

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