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

Rosendahl J, Kirsten H, Hegyi E, Kovacs P, Weiss FU, Laumen H, Lichtner P, Ruffert C, Chen JM, Masson E, Beer S, Zimmer C, Seltsam K, Alguel H, Buehler F, Bruno MJ, Bugert P, Burkhardt R, Cavestro GM, Cichoz-Lach H, Farre A, Frank J, Gambaro G, Gimpfl S, Grallert H, Griesmann H, Grützmann R, Hellerbrand C, Hegyi P, Hollenbach M, Iordache S, Jurkowska G, Keim V, Kiefer F, Krug S, Landt O, Di Leo M, Lerch MM, Levy P, Loeffler M, Loehr M, Ludwig M, Macek M, Malats N, Malecka-Panas E, Malerba G, Mann K, Mayerle J, Mohr S, Te Morsche RHM, Motyka M, Mueller S, Mueller T, Noethen MM, Pedrazzoli S, Pereira SP, Peters A, Pfuetzer R, Real FX, Rebours V, Ridinger M, Rietschel M, Roesmann E, Saftoiu A, Schneider A, Schulz HU, Soranzo N, Soyka M, Simon P, Skipworth J, Stickel F, Strauch K, Stumvoll M, Testoni PA, Toenjes A, Werner L, Werner J, Wodarz N, Ziegler M, Masamune A, Moessner J, Ferec C, Michl P, Drenth JPH, Witt H, Scholz M, Sahin-Toth M (2017)

Publication Type: Journal article

Publication year: 2017

Journal

DOI: 10.1136/gutjnl-2017-314454

Abstract

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.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.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.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.

Authors with CRIS profile

Involved external institutions

Ruprecht-Karls-Universität Heidelberg Germany (DE) Università Vita-Salute San Raffaele (UniSR) Italy (IT) Medizinische Universität Innsbruck Austria (AT) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) Universitätsklinikum Regensburg Germany (DE) Technische Universität München (TUM) Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) University of Białystok Poland (PL) Beaujon Hospital / Hôpital Beaujon France (FR) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University of Verona / Università degli Studi di Verona Italy (IT) Universität Leipzig Germany (DE) Karolinska Institute Sweden (SE) Grigore T. Popa University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie "Grigore T. Popa" (UMF Iași) Romania (RO) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Klinikum Döbeln Germany (DE) Otto-von-Guericke-Universität Magdeburg Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Universität Greifswald Germany (DE) Universität Regensburg Germany (DE) Tohoku University Japan (JP) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) University College London (UCL) United Kingdom (GB) Centro de Investigación Biomédica en Red (CIBER) Spain (ES) Hospital de la Santa Creu i Sant Pau Spain (ES) Ludwig-Maximilians-Universität (LMU) Germany (DE) Medical University of Łódź / Uniwersytet Medyczny w Łodzi Poland (PL) Boston University United States (USA) (US) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) University of Padua / Universita degli Studi di Padova Italy (IT) Universitätsspital Zürich (USZ) Switzerland (CH) University of Pécs / Pécsi Tudományegyetem Hungary (HU) Universitätsklinikum Leipzig Germany (DE) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) TIB MOLBIOL Syntheselabor GmbH Germany (DE) Medical University of Lublin / Uniwersytet Medyczny w Lublinie Poland (PL)

How to cite

APA:

Rosendahl, J., Kirsten, H., Hegyi, E., Kovacs, P., Weiss, F.U., Laumen, H.,... Sahin-Toth, M. (2017). Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. Gut. https://dx.doi.org/10.1136/gutjnl-2017-314454

MLA:

Rosendahl, Jonas, et al. "Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis." Gut (2017).

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