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Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
J. Rosendahl, H. Kirsten, E. Hegyi, P. Kovacs, FU. Weiss, H. Laumen, P. Lichtner, C. Ruffert, JM. Chen, E. Masson, S. Beer, C. Zimmer, K. Seltsam, H. Algül, F. Bühler, MJ. Bruno, P. Bugert, R. Burkhardt, GM. Cavestro, H. Cichoz-Lach, A. Farré, J....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc18033801
Online
Plný text
NLK
ProQuest Central
od 1960-03-01 do Před 6 měsíci
Health & Medicine (ProQuest)
od 1960-03-01 do Před 6 měsíci
- MeSH
- alkoholická pankreatitida * epidemiologie genetika MeSH
- chymotrypsin genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa epidemiologie MeSH
OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
Biology and Genetics Department of Life and Reproduction Sciences University of Verona Verona Italy
Clinic for Internal Medicine Hospital Döbeln Döbeln Germany
Department of Digestive Tract Diseases Medical University of Łódź Łódź Poland
Department of Gastroenterology and Hepatology Radboud umc Nijmegen The Netherlands
Department of Gastroenterology and Hepatology University Hospital of Zürich Zürich Switzerland
Department of Gastroenterology and Internal Medicine Medical University Bialystok Bialystok Poland
Department of Gastroenterology Hospital de la Santa Creu i Sant Pau Barcelona Spain
Department of Gastroenterology Medical University of Lublin Lublin Poland
Department of Gastroenterology Technische Universität München Munich Germany
Department of General Visceral and Transplant Surgery Ludwig Maximilian University Munich Germany
Department of Internal Medicine 1 Martin Luther University Halle Germany
Department of Internal Medicine 1 University Hospital Regensburg Regensburg Germany
Department of Internal Medicine A Ernst Moritz Arndt University Greifswald Germany
Department of Medical and Surgical Sciences 4 Surgical Clinic University of Padua Padua Italy
Department of Medicine 2 University Hospital Ludwig Maximilians University Munich Munich Germany
Department of Pediatrics 1 Medical University Innsbruck Austria
Department of Psychiatry University of Regensburg Regensburg Germany
Department of Surgery and Interventional Science University College London London UK
Department of Surgery Otto von Guericke University Magdeburg Magdeburg Germany
Division of Gastroenterology Tohoku University Graduate School of Medicine SendaiMiyagi Japan
Else Kröner Fresenius Zentrum für Ernährungsmedizin Freising Germany
Etablissement Français du Sang Bretagne
Faculté de Médecine et des Sciences de la Santé Université de Bretagne Occidentale
Gastrocentrum Karolinska Institutet CLINTEC Stockholm Sweden
Institut National de la Santé et de la Recherche Médicale U1078
Leipzig University Medical Center IFB Adiposity Diseases University of Leipzig Leipzig Germany
Citace poskytuje Crossref.org
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- $a Rosendahl, Jonas $u Department of Internal Medicine I, Martin Luther University, Halle, Germany. Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
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- $a Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis / $c J. Rosendahl, H. Kirsten, E. Hegyi, P. Kovacs, FU. Weiss, H. Laumen, P. Lichtner, C. Ruffert, JM. Chen, E. Masson, S. Beer, C. Zimmer, K. Seltsam, H. Algül, F. Bühler, MJ. Bruno, P. Bugert, R. Burkhardt, GM. Cavestro, H. Cichoz-Lach, A. Farré, J. Frank, G. Gambaro, S. Gimpfl, H. Grallert, H. Griesmann, R. Grützmann, C. Hellerbrand, P. Hegyi, M. Hollenbach, S. Iordache, G. Jurkowska, V. Keim, F. Kiefer, S. Krug, O. Landt, MD. Leo, MM. Lerch, P. Lévy, M. Löffler, M. Löhr, M. Ludwig, M. Macek, N. Malats, E. Malecka-Panas, G. Malerba, K. Mann, J. Mayerle, S. Mohr, RHM. Te Morsche, M. Motyka, S. Mueller, T. Müller, MM. Nöthen, S. Pedrazzoli, SP. Pereira, A. Peters, R. Pfützer, FX. Real, V. Rebours, M. Ridinger, M. Rietschel, E. Rösmann, A. Saftoiu, A. Schneider, HU. Schulz, N. Soranzo, M. Soyka, P. Simon, J. Skipworth, F. Stickel, K. Strauch, M. Stumvoll, PA. Testoni, A. Tönjes, L. Werner, J. Werner, N. Wodarz, M. Ziegler, A. Masamune, J. Mössner, C. Férec, P. Michl, J. P H Drenth, H. Witt, M. Scholz, M. Sahin-Tóth, . ,
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- $a OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
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- $a Kirsten, Holger $u Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. Department of Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.
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- $a Hegyi, Eszter $u Department of Molecular and Cell Biology, Center for Exocrine Disorders, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA.
- 700 1_
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- $a Chen, Jian-Min $u Institut National de la Santé et de la Recherche Médicale (INSERM) U1078; Etablissement Français du Sang (EFS) - Bretagne; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale; Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Morvan, Brest, France.
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- $a Beer, Sebastian $u Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Gimpfl, Sebastian $u Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
- 700 1_
- $a Grallert, Harald $u Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Werner, Lena $u Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
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- 700 1_
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- 700 1_
- $a Ziegler, Martin $u Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
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- $a Witt, Heiko $u Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
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