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Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study
  1. Monique H Derikx1,
  2. Peter Kovacs2,
  3. Markus Scholz3,4,
  4. Emmanuelle Masson5,6,7,8,
  5. Jian-Min Chen5,6,7,8,
  6. Claudia Ruffert9,
  7. Peter Lichtner10,
  8. Rene H M te Morsche1,
  9. Giulia Martina Cavestro11,
  10. Hana Algül13,
  11. Thomas Berg14,
  12. Hans Bödeker15,
  13. Matthias Blüher2,
  14. Marco J Bruno16,
  15. Stephan Buch17,
  16. Peter Bugert18,
  17. Halina Cichoz-Lach19,
  18. Andrzej Dabrowski20,
  19. Antoni Farré21,
  20. Josef Frank22,
  21. Anita Gasiorowska23,
  22. Andrea Geisz24,
  23. Elisabetta Goni11,
  24. Johannes Grothaus25,
  25. Robert Grützmann26,
  26. Stephan Haas27,
  27. Jochen Hampe17,
  28. Claus Hellerbrand28,
  29. Peter Hegyi24,
  30. Dominik Huster29,
  31. Mihai Ioana30,
  32. Sevastitia Iordache31,
  33. Grazyna Jurkowska20,
  34. Volker Keim9,
  35. Olfert Landt32,
  36. Milena Di Leo11,
  37. Markus M Lerch33,
  38. Philippe Lévy34,
  39. Matthias J Löhr27,
  40. Milan Macek35,
  41. Nuria Malats36,
  42. Ewa Malecka-Panas23,
  43. Alberto Mariani11,
  44. Davide Martorana37,
  45. Julia Mayerle33,
  46. Josefina Mora38,
  47. Joachim Mössner9,
  48. Sebastian Müller39,
  49. Johann Ockenga40,
  50. Jana Paderova35,
  51. Sergio Pedrazzoli41,
  52. Stephen P Pereira42,
  53. Roland Pfützer43,
  54. Francisco X Real44,
  55. Vinciane Rebours34,
  56. Monika Ridinger28,
  57. Marcella Rietschel22,
  58. Kerstin Rohde9,
  59. Stephan Sack45,
  60. Adrian Saftoiu31,
  61. Alexander Schneider46,
  62. Hans-Ulrich Schulz47,
  63. Michael Soyka48,
  64. Peter Simon33,
  65. James Skipworth49,
  66. Felix Stickel50,
  67. Michael Stumvoll2,51,
  68. Pier Alberto Testoni11,
  69. Anke Tönjes2,51,
  70. Matthias Treiber13,
  71. Frank Ulrich Weiss33,
  72. Jens Werner52,
  73. Norbert Wodarz28,
  74. Claude Férec5,6,7,8,
  75. Joost P H Drenth1,
  76. Heiko Witt12,
  77. Jonas Rosendahl9
  1. 1Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, The Netherlands
  2. 2Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
  3. 3Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  4. 4LIFE- Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
  5. 5Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France
  6. 6Etablissement Français du Sang (EFS)—Bretagne, Brest, France
  7. 7Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
  8. 8Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
  9. 9Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany
  10. 10Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany
  11. 11Unità Operativa di Gastroenterologia ed Endoscopia Digestiva, Università Vita Salute San Raffaele e IRCCS Ospedale San Raffaele, Milan, Italy
  12. 12Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Zentralinstitut für Ernährungs- und Lebensmittelforschung (ZIEL) & Paediatric Nutritional Medicine, Technische Universität München (TUM), Munich, Germany
  13. 13II. Medizinische Klinik, Klinikum rechts der Isar of the Technical University Munich, Munich, Germany
  14. 14Department of Internal Medicine, Neurology and Dermatology, Clinic of Gastroenterology and Rheumatology, Division of Hepatology, University of Leipzig, Leipzig, Germany
  15. 15Hospital Freiberg, Academic Hospital of the Technical University Dresden, Clinic for Internal Medicine, Freiberg, Germany
  16. 16Department of Gastroenterology & Hepatology, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands
  17. 17Medical Department I, University Hospital Dresden, TU Dresden, Dresden, Germany
  18. 18Institute of Transfusion Medicine and Immunology, Medical Faculty of Mannheim University of Heidelberg, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany
  19. 19Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
  20. 20Department of Gastroenterology and Internal Medicine, Medical University Bialystok, Bialystok, Poland
  21. 21Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  22. 22Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany
  23. 23Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
  24. 24First Department of Medicine, University of Szeged, Szeged, Hungary
  25. 25Department of Medicine I, Altona General Hospital, Hamburg, Germany
  26. 26Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
  27. 27Gastrocentrum, Karolinska Institutet CLINTEC, Stockholm, Sweden
  28. 28Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
  29. 29Evangelisches Diakonissenkrankenhaus Leipzig, Academic Hospital of the University of Leipzig, Leipzig, Germany
  30. 30Molecular and Cellular Biology Department, University of Medicine and Pharmacy Craiova, Craiova, Romania
  31. 31Department of Internal Medicine and Gastroenterology, University of Medicine and Pharmacy, Craiova, Romania
  32. 32TIB MOLBIOL, Berlin, Germany
  33. 33Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
  34. 34Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, AP-HP, Clichy, France
  35. 35Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
  36. 36Grupo de Epidemiología Genética y Molecular Programa de Genética del Cáncer Humano Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
  37. 37Unit of Molecular Genetics, University Hospital of Parma, Parma, Italy
  38. 38Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  39. 39Department of Internal Medicine, Salem Medical Centre and Centre for Alcohol Research, University of Heidelberg, Heidelberg, Germany
  40. 40Medical Clinic II, Internal Medicine, Gastroenterology, Endocrinology and Nutritional Medicine, Klinikum Links der Weser, Klinikum Bremen Mitte, Bremen, Germany
  41. 41IV Surgical Clinic, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy
  42. 42UCL Institute for Liver and Digesive Health, Division of Medicine, University College London, London, UK
  43. 43Clinic for Internal Medicine, Hospital Döbeln, Döbeln, Germany
  44. 44Epithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
  45. 45Clinic for Internal Medicine II, Ev. Klinikum Paul-Gerhardt-Stift, Paul-Gerhardt-Diakonie Hospital and Care GmbH, Lutherstadt Wittenberg, Germany
  46. 46Department of Gastroenterology, Hepatology, Infectious Diseases, Medical Faculty of Mannheim University of Heidelberg, Mannheim, Germany
  47. 47Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  48. 48Psychiatric Hospital, University of Munich, Munich, Germany
  49. 49Department of Surgery and Interventional Science, University College London, London, UK
  50. 50Department of Visceral Surgery and Medicine, Inselspital Bern, Berne, Switzerland
  51. 51Department of Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany
  52. 52Department of General Surgery, University of Heidelberg, Heidelberg, Germany
  1. Correspondence to Dr Jonas Rosendahl, Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University Clinic of Leipzig, Liebigstraße 20, Leipzig 04103, Germany; jonas.rosendahl{at}medizin.uni-leipzig.de

Abstract

Objective Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort.

Design We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype–phenotype relationships.

Results Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51).

Conclusions The single-nucleotide polymorphisms rs10273639 at the PRSS1–PRSS2 locus and rs7057398 and rs12688220 at the CLDN2MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.

  • CHRONIC PANCREATITIS
  • GENETIC POLYMORPHISMS
  • PANCREATITIS
  • TRYPSINOGEN

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