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Original article
Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
  1. Jonas Rosendahl1,2,
  2. Holger Kirsten3,4,5,
  3. Eszter Hegyi6,
  4. Peter Kovacs7,
  5. Frank Ulrich Weiss8,
  6. Helmut Laumen9,
  7. Peter Lichtner10,
  8. Claudia Ruffert1,
  9. Jian-Min Chen11,
  10. Emmanuelle Masson11,
  11. Sebastian Beer2,
  12. Constantin Zimmer2,
  13. Katharina Seltsam2,
  14. Hana Algül12,
  15. Florence Bühler9,
  16. Marco J Bruno13,
  17. Peter Bugert14,
  18. Ralph Burkhardt4,15,
  19. Giulia Martina Cavestro16,
  20. Halina Cichoz-Lach17,
  21. Antoni Farré18,
  22. Josef Frank19,
  23. Giovanni Gambaro20,
  24. Sebastian Gimpfl9,
  25. Harald Grallert21,22,23,
  26. Heidi Griesmann1,
  27. Robert Grützmann24,
  28. Claus Hellerbrand25,
  29. Péter Hegyi26,27,
  30. Marcus Hollenbach1,
  31. Sevastitia Iordache28,
  32. Grazyna Jurkowska29,
  33. Volker Keim2,
  34. Falk Kiefer30,
  35. Sebastian Krug1,
  36. Olfert Landt31,
  37. Milena Di Leo16,
  38. Markus M Lerch8,
  39. Philippe Lévy32,
  40. Markus Löffler3,4,
  41. Matthias Löhr33,
  42. Maren Ludwig9,
  43. Milan Macek34,
  44. Nuria Malats35,36,
  45. Ewa Malecka-Panas37,
  46. Giovanni Malerba38,
  47. Karl Mann30,
  48. Julia Mayerle39,
  49. Sonja Mohr9,
  50. Rene H M te Morsche40,
  51. Marie Motyka9,
  52. Sebastian Mueller41,
  53. Thomas Müller42,
  54. Markus M Nöthen43,44,
  55. Sergio Pedrazzoli45,
  56. Stephen P Pereira46,
  57. Annette Peters22,23,47,
  58. Roland Pfützer48,
  59. Francisco X Real36,49,50,
  60. Vinciane Rebours32,
  61. Monika Ridinger51,
  62. Marcella Rietschel19,
  63. Eva Rösmann9,
  64. Adrian Saftoiu28,
  65. Alexander Schneider52,
  66. Hans-Ulrich Schulz53,
  67. Nicole Soranzo54,55,
  68. Michael Soyka56,
  69. Peter Simon8,
  70. James Skipworth57,
  71. Felix Stickel58,
  72. Konstantin Strauch59,60,
  73. Michael Stumvoll7,61,
  74. Pier Alberto Testoni16,
  75. Anke Tönjes61,
  76. Lena Werner9,
  77. Jens Werner62,
  78. Norbert Wodarz51,
  79. Martin Ziegler9,
  80. Atsushi Masamune63,
  81. Joachim Mössner2,
  82. Claude Férec11,
  83. Patrick Michl1,
  84. Joost P H Drenth40,
  85. Heiko Witt9,
  86. Markus Scholz3,4,
  87. Miklós Sahin-Tóth6
  88. On behalf of all members of the PanEuropean Working group on ACP
  1. 1 Department of Internal Medicine I, Martin Luther University, Halle, Germany
  2. 2 Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany
  3. 3 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  4. 4 LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
  5. 5 Department of Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
  6. 6 Department of Molecular and Cell Biology, Center for Exocrine Disorders, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
  7. 7 Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany
  8. 8 Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany
  9. 9 Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany
  10. 10 Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany
  11. 11 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
  12. 12 Department of Gastroenterology, Technische Universität München (TUM), Munich, Germany
  13. 13 Department of Gastroenterology & Hepatology, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands
  14. 14 Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany
  15. 15 Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
  16. 16 Division of Gastroenterology and Gastrointestinal Endoscopy, Vita Salute San Raffaele University - San Raffaele Scientific Institute, Milan, Italy
  17. 17 Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
  18. 18 Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  19. 19 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany
  20. 20 Division of Nephrology and Dialysis, Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy
  21. 21 Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  22. 22 Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  23. 23 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
  24. 24 Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Chirurgische Klinik, Erlangen, Germany
  25. 25 Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
  26. 26 Institute for Translational Medicine and First Department of Internal Medicine, University of Pécs, Pécs, Hungary
  27. 27 HAS-SZTE, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
  28. 28 Department of Internal Medicine and Gastroenterology, University of Medicine and Pharmacy, Craiova, Romania
  29. 29 Department of Gastroenterology and Internal Medicine, Medical University Bialystok, Bialystok, Poland
  30. 30 Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany
  31. 31 TIB MOLBIOL, Berlin, Germany
  32. 32 Pôle des Maladies de l’Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, AP-HP, Clichy, France
  33. 33 Gastrocentrum, Karolinska Institutet CLINTEC, Stockholm, Sweden
  34. 34 Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
  35. 35 Grupo de Epidemiología Genética y Molecular Programa de Genética del Cáncer Humano Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
  36. 36 CIBERONC, Spain
  37. 37 Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland
  38. 38 Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy
  39. 39 Department of Medicine II, University Hospital,Ludwig-Maximilians-University Munich, Munich, Germany
  40. 40 Department of Gastroenterology and Hepatology, Radboud umc, Nijmegen, The Netherlands
  41. 41 Department of Internal Medicine, Salem Medical Centre and Centre for Alcohol Research, University of Heidelberg, Heidelberg, Germany
  42. 42 Department of Pediatrics I, Medical University, Innsbruck, Austria
  43. 43 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
  44. 44 Institute of Human Genetics, University of Bonn, Bonn, Germany
  45. 45 Department of Medical and Surgical Sciences, IV Surgical Clinic, University of Padua, Padua, Italy
  46. 46 Division of Medicine, UCL Institute for Liver and Digestive Health, University College London, London, UK
  47. 47 DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
  48. 48 Clinic for Internal Medicine, Hospital Döbeln, Döbeln, Germany
  49. 49 Epithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
  50. 50 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  51. 51 Department of Psychiatry, University of Regensburg, Regensburg, Germany
  52. 52 Department of Gastroenterology, Hepatology, Infectious Diseases, Medical Faculty of Mannheim University of Heidelberg, Mannheim, Germany
  53. 53 Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  54. 54 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  55. 55 Department of Haematology, University of Cambridge, Cambridge, UK
  56. 56 Psychiatric Hospital, University of Munich, Munich, Germany
  57. 57 Department of Surgery and Interventional Science, University College London, London, UK
  58. 58 Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland
  59. 59 Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
  60. 60 Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
  61. 61 Department of Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany
  62. 62 Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
  63. 63 Division of Gastroenterology, Tohoku University Graduate School of Medicine, SendaiMiyagi, Japan
  1. Correspondence to Professor Jonas Rosendahl, Department of Internal Medicine, Neurology and Dermatology Division of Gastroenterology and Rheumatology, University Clinic of Leipzig Liebigstraße 20, 04103 Leipzig, Germany; jonas.rosendahl{at}medizin.uni-leipzig.de

Abstract

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.

  • Genome wide association study
  • chronic pancreatitis
  • genetic rearrangement

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Footnotes

  • JPHD, HW, MS and MS-T contributed equally to the supervision of the work.

  • JR and HK contributed equally.

  • Contributors JR, PK, JPHD, HW, MS, MS-T and HK conceived, designed and directed the study. JR, EH, FUW, PL, CR and CZ performed genotyping. JR, HK and MS-T drafted and revised the manuscript with substantial help from FXR, JPHD, HW, PK, EH and MS. MS and HK performed bioinformatics work. JR , EH , FUW, HL, PL, CR, JMC, EM, HW, MS, MS-T and HK designed, performed and interpreted genetic analyses. EH and MS-T carried out functional analysis. All other co-authors recruited study subjects, collected clinical data and/or provided genomic DNA samples. All authors approved the final manuscript and contributed critical revisions to its intellectual content.

  • Funding This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants RO 3929/1–1, RO 3929/2-1 and RO3929/5-1 (to JR), Wi 2036/2-2 and Wi 2036/2-3 (to HW) and SFB 1052 (to MB, MS, AT, PK), SFB 1052 C01, B01, B03; SPP 1629 TO 718/2-1 (to AT) by a grant of the Colora Stiftung gGmbH (to JR), the Else Kröner-Fresenius-Foundation (EKFS) (to HW), NIH grants R01DK058088, R01DK082412; and R01DK095753 (to MS-T), a grant from the National Pancreas Foundation (to EH), the Institut National de la Santé et de la Recherche Médicale (INSERM; to CF), the Programme Hospitalier de Recherche Clinique (PHRC R 08-04; to CF), the French Association des Pancréatites Chroniques Héréditaires (to CF), the Council of Scientific and Industrial Research (CSIR) (to CF), by grants of the European Regional Development Fund (ERDF) V-630-F-150-2012/133 and V630-S-150-2012/132 (to FUW), by grants 310030_138747 and 310030_169196 from the Swiss National Funds (to FS) and by grants RTICC from Instituto de Salud Carlos III (RD12/0036/0034) and SAF 2015–70857 from Ministerio de Economía y Competitividad (Madrid, Spain) (co-funded by the ERDF-EU) (to FXR) and Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (Grant #PI1501573) (to NM). SPP was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by funds of the Free State of Saxony within the framework of the excellence initiative (project numbers 713-241202, 14505/2470, 14575/2470). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was financed by a grant from the BMBF to the German Center for Diabetes Research (DZD) and a grant from the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany). It was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethic Committee of the University of Leipzig.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All chip data are available upon request.

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