Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis,Gut

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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
Gut ( IF 23.0 ) Pub Date : 2017-07-28 , DOI: 10.1136/gutjnl-2017-314454
Jonas Rosendahl _{1,

2} , Holger Kirsten _{3,

4,

5} , Eszter Hegyi ₆ , Peter Kovacs ₇ , Frank Ulrich Weiss ₈ , Helmut Laumen ₉ , Peter Lichtner ₁₀ , Claudia Ruffert ₁ , Jian-Min Chen ₁₁ , Emmanuelle Masson ₁₁ , Sebastian Beer ₂ , Constantin Zimmer ₂ , Katharina Seltsam ₂ , Hana Algül ₁₂ , Florence Bühler ₉ , Marco J Bruno ₁₃ , Peter Bugert ₁₄ , Ralph Burkhardt _{4,

15} , Giulia Martina Cavestro ₁₆ , Halina Cichoz-Lach ₁₇ , Antoni Farré ₁₈ , Josef Frank ₁₉ , Giovanni Gambaro ₂₀ , Sebastian Gimpfl ₉ , Harald Grallert _{21,

22,

23} , Heidi Griesmann ₁ , Robert Grützmann ₂₄ , Claus Hellerbrand ₂₅ , Péter Hegyi _{26,

27} , Marcus Hollenbach ₁ , Sevastitia Iordache ₂₈ , Grazyna Jurkowska ₂₉ , Volker Keim ₂ , Falk Kiefer ₃₀ , Sebastian Krug ₁ , Olfert Landt ₃₁ , Milena Di Leo ₁₆ , Markus M Lerch ₈ , Philippe Lévy ₃₂ , Markus Löffler _{3,

4} , Matthias Löhr ₃₃ , Maren Ludwig ₉ , Milan Macek ₃₄ , Nuria Malats _{35,

36} , Ewa Malecka-Panas ₃₇ , Giovanni Malerba ₃₈ , Karl Mann ₃₀ , Julia Mayerle ₃₉ , Sonja Mohr ₉ , Rene H M Te Morsche ₄₀ , Marie Motyka ₉ , Sebastian Mueller ₄₁ , Thomas Müller ₄₂ , Markus M Nöthen _{43,

44} , Sergio Pedrazzoli ₄₅ , Stephen P Pereira ₄₆ , Annette Peters _{22,

23,

47} , Roland Pfützer ₄₈ , Francisco X Real _{36,

49,

50} , Vinciane Rebours ₃₂ , Monika Ridinger ₅₁ , Marcella Rietschel ₁₉ , Eva Rösmann ₉ , Adrian Saftoiu ₂₈ , Alexander Schneider ₅₂ , Hans-Ulrich Schulz ₅₃ , Nicole Soranzo _{54,

55} , Michael Soyka ₅₆ , Peter Simon ₈ , James Skipworth ₅₇ , Felix Stickel ₅₈ , Konstantin Strauch _{59,

60} , Michael Stumvoll _{7,

61} , Pier Alberto Testoni ₁₆ , Anke Tönjes ₆₁ , Lena Werner ₉ , Jens Werner ₆₂ , Norbert Wodarz ₅₁ , Martin Ziegler ₉ , Atsushi Masamune ₆₃ , Joachim Mössner ₂ , Claude Férec ₁₁ , Patrick Michl ₁ , Joost P H Drenth ₄₀ , Heiko Witt ₉ , Markus Scholz _{3,

4} , Miklós Sahin-Tóth ₆ ,

Affiliation

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.
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.
Department of Molecular and Cell Biology, Center for Exocrine Disorders, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA.
Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
Department of Internal Medicine A, Ernst-Moritz-Arndt University, Greifswald, Germany.
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.
Institute of Human Genetics, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
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.
Department of Gastroenterology, Technische Universität München (TUM), Munich, Germany.
Department of Gastroenterology & Hepatology, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany.
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
Division of Gastroenterology and Gastrointestinal Endoscopy, Vita Salute San Raffaele University - San Raffaele Scientific Institute, Milan, Italy.
Department of Gastroenterology, Medical University of Lublin, Lublin, Poland.
Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
Division of Nephrology and Dialysis, Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
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.
Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Chirurgische Klinik, Erlangen, Germany.
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Institute for Translational Medicine and First Department of Internal Medicine, University of Pécs, Pécs, Hungary.
HAS-SZTE, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary.
Department of Internal Medicine and Gastroenterology, University of Medicine and Pharmacy, Craiova, Romania.
Department of Gastroenterology and Internal Medicine, Medical University Bialystok, Bialystok, Poland.
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
TIB MOLBIOL, Berlin, Germany.
Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, AP-HP, Clichy, France.
Gastrocentrum, Karolinska Institutet CLINTEC, Stockholm, Sweden.
Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
Grupo de Epidemiología Genética y Molecular Programa de Genética del Cáncer Humano Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
CIBERONC, Spain.
Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland.
Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
Department of Medicine II, University Hospital,Ludwig-Maximilians-University Munich, Munich, Germany.
Department of Gastroenterology and Hepatology, Radboud umc, Nijmegen, The Netherlands.
Department of Internal Medicine, Salem Medical Centre and Centre for Alcohol Research, University of Heidelberg, Heidelberg, Germany.
Department of Pediatrics I, Medical University, Innsbruck, Austria.
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Medical and Surgical Sciences, IV Surgical Clinic, University of Padua, Padua, Italy.
Division of Medicine, UCL Institute for Liver and Digestive Health, University College London, London, UK.
DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
Clinic for Internal Medicine, Hospital Döbeln, Döbeln, Germany.
Epithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Department of Psychiatry, University of Regensburg, Regensburg, Germany.
Department of Gastroenterology, Hepatology, Infectious Diseases, Medical Faculty of Mannheim University of Heidelberg, Mannheim, Germany.
Department of Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Department of Haematology, University of Cambridge, Cambridge, UK.
Psychiatric Hospital, University of Munich, Munich, Germany.
Department of Surgery and Interventional Science, University College London, London, UK.
Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland.
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
Department of Internal Medicine, Neurology and Dermatology, Division of Endocrinology, University of Leipzig, Leipzig, Germany.
Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany.
Division of Gastroenterology, Tohoku University Graduate School of Medicine, SendaiMiyagi, Japan.

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.

中文翻译：

全基因组关联研究确定 CTRB1-CTRB2 基因座倒位以降低酒精性和非酒精性慢性胰腺炎的风险

目的酒精相关性胰腺炎与胃肠道疾病中不成比例的大量住院治疗相关。尽管其临床重要性，但对酒精性慢性胰腺炎（CP）的遗传易感性却知之甚少。为了识别酒精性脑瘫的风险基因并评估其与非酒精性脑瘫的相关性，我们进行了全基因组关联研究和一个新的胰腺炎基因座的功能表征。使用 Illumina 技术对 1959 名欧洲酒精性 CP 患者和来自 KORA、LIFE 和 INCIPE 研究的基于人群的对照 (n=4708) 以及来自 GESGA 联盟的慢性酗酒者 (n=1332) 进行筛选。为了进行复制，使用了三个欧洲队列，其中包括来自同一国家的 1650 名非酒精性 CP 患者和 6695 名对照者。结果我们在酒精性脑瘫患者中复制了之前报道的风险位点 CLDN2-MORC4、CTRC、PRSS1-PRSS2 和 SPINK1。我们将 CTRB1-CTRB2（胰凝乳蛋白酶 B1 和 B2）确定为一个新的风险位点，其先导单核苷酸多态性 (SNP) rs8055167（OR 1.35，95% CI 1.23 至 1.6）。我们发现 CTRB1-CTRB2 基因座中的 16.6 kb 倒位与 CP 相关 SNP 连锁不平衡，最好用 rs8048956 标记。这种关联在三个独立的欧洲非酒精性 CP 队列中得到了验证，该队列由 1650 名患者和 6695 名对照者组成（OR 1.62，95% CI 1.42 至 1.86）。这种倒位改变了 CTRB1 和 CTRB2 亚型的表达比例，从而影响保护性胰蛋白酶原降解并最终影响胰腺炎风险。结论 CTRB1-CTRB2 基因座的倒位改变了酒精性和非酒精性 CP 的风险，表明这些炎症性疾病涉及常见的病理机制。

更新日期：2017-07-28

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