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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: 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
Zeitschrift: Gut
Jahr der Veröffentlichung: 2017
ISSN: 0017-5749


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.


FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Grützmann, Robert Prof. Dr.
Lehrstuhl für Allgemein- und Viszeralchirurgie


Einrichtungen weiterer Autorinnen und Autoren

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


Zitierweisen

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).

BibTeX: 

Zuletzt aktualisiert 2018-21-11 um 10:08