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

CIBERONC Spain

Clinic for Internal Medicine Hospital Döbeln Döbeln Germany

Departament de Ciències Experimentals i de la Salut Universitat Pompeu Fabra Barcelona Spain

Department of Addictive Behavior and Addiction Medicine Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

Department of Biology and Medical Genetics University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Cell Therapy Fraunhofer Institute for Cell Therapy and Immunology Leipzig Germany

Department of Digestive Tract Diseases Medical University of Łódź Łódź Poland

Department of Gastroenterology and Hepatology Erasmus Medical Centre University Medical Centre Rotterdam Rotterdam The Netherlands

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 Hepatology Infectious Diseases Medical Faculty of Mannheim University of Heidelberg Mannheim Germany

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 Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Haematology University of Cambridge Cambridge UK

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 Internal Medicine and Gastroenterology University of Medicine and Pharmacy Craiova Romania

Department of Internal Medicine Neurology and Dermatology Division of Endocrinology University of Leipzig Leipzig Germany

Department of Internal Medicine Neurology and Dermatology Division of Gastroenterology University of Leipzig Leipzig Germany

Department of Internal Medicine Salem Medical Centre and Centre for Alcohol Research University of Heidelberg Heidelberg 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 Molecular and Cell Biology Center for Exocrine Disorders Boston University Henry M Goldman School of Dental Medicine Boston Massachusetts USA

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 and Gastrointestinal Endoscopy Vita Salute San Raffaele University San Raffaele Scientific Institute Milan Italy

Division of Gastroenterology Tohoku University Graduate School of Medicine SendaiMiyagi Japan

Division of Medicine UCL Institute for Liver and Digestive Health University College London London UK

Division of Nephrology and Dialysis Institute of Internal Medicine Renal Program Columbus Gemelli University Hospital Catholic University Rome Italy

DZHK Partner Site Munich Heart Alliance Munich Germany

Else Kröner Fresenius Zentrum für Ernährungsmedizin Freising Germany

Epithelial Carcinogenesis Group Molecular Pathology Programme Centro Nacional de Investigaciones Oncológicas Madrid Spain

Gastrocentrum Karolinska Institutet CLINTEC Stockholm Sweden

German Center for Diabetes Research Neuherberg Germany

Grupo de Epidemiología Genética y Molecular Programa de Genética del Cáncer Humano Centro Nacional de Investigaciones Oncológicas Madrid Spain

HAS SZTE Momentum Gastroenterology Multidisciplinary Research Group Szeged Hungary

Institut National de la Santé et de la Recherche Médicale Brest Hôpital Morvan Brest France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute for Translational Medicine and 1st Department of Internal Medicine University of Pécs Pécs Hungary

Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Genetic Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Human Genetics Helmholtz Centre Munich German Research Centre for Environmental Health Neuherberg Germany

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Laboratory Medicine Clinical Chemistry and Molecular Diagnostics University Hospital Leipzig Leipzig Germany

Institute of Medical Informatics Biometry and Epidemiology Chair of Genetic Epidemiology Ludwig Maximilians Universität Munich Germany

Institute of Transfusion Medicine and Immunology Medical Faculty Mannheim Heidelberg University German Red Cross Blood Service of Baden Württemberg Mannheim Germany

Leipzig University Medical Center IFB Adiposity Diseases University of Leipzig Leipzig Germany

LIFE Leipzig Research Center for Civilization Diseases University of Leipzig Leipzig Germany

Pôle des Maladies de l'Appareil Digestif Service de Gastroentérologie Pancréatologie Hôpital Beaujon AP HP Clichy France

Psychiatric Hospital University of Munich Munich Germany

Research Unit of Molecular Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

The Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridge UK

TIB MOLBIOL Berlin Germany

Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen Nürnberg Chirurgische Klinik Erlangen Germany

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Gut. 2018 Jul;67(7):1368-1369. doi: 10.1136/gutjnl-2017-315180. PubMed

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Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia

Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report