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Rosendahl, J.* ; Kirsten, H.* ; Hegyi, E.* ; Kovacs, P.* ; Weiss, F.U.* ; Laumen, H.* ; Lichtner, P. ; Ruffert, C.* ; Chen, J.M.* ; Masson, E.* ; Beer, S.* ; Zimmer, C.* ; Seltsam, K.* ; Algül, H.* ; Bühler, F.* ; Bruno, M.J.* ; Bugert, P.* ; Burkhardt, R.* ; Cavestro, G.M.* ; Cichoz-Lach, H.* ; Farré, 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.* ; Leo, M.D.* ; Lerch, M.M.* ; Lévy, P.* ; Löffler, M.* ; Löhr, M.* ; Ludwig, M.* ; Macek, M.* ; Malats, N.* ; Malecka-Panas, E.* ; Malerba, G.* ; Mann, K.* ; Mayerle, J.* ; Mohr, S.* ; Te Morsche, R.H.M.* ; Motyka, M.* ; Mueller, S.* ; Müller, T.* ; Nöthen, M.M.* ; Pedrazzoli, S.* ; Pereira, S.P.* ; Peters, A. ; Pfützer, R.* ; Real, F.X.* ; Rebours, V.* ; Ridinger, M.* ; Rietschel, M.* ; Rösmann, E.* ; Saftoiu, A.* ; Schneider, A.* ; Schulz, H.U.* ; Soranzo, N.* ; Soyka, M.* ; Simon, P.* ; Skipworth, J.* ; Stickel, F.* ; Strauch, K. ; Stumvoll, M.* ; Testoni, P.A.* ; Tönjes, A.* ; Werner, L.* ; Werner, J.* ; Wodarz, N.* ; Ziegler, M.* ; Masamune, A.* ; Mössner, J.* ; Férec, C.* ; Michl, P.* ; P H Drenth, J.* ; Witt, H.* ; Scholz, M.* ; Sahin-Tóth, M.*

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

Gut 67, 1855–186 (2018)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 16.6kb 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genome Wide Association Study ; Chronic Pancreatitis ; Genetic Rearrangement; Hereditary Pancreatitis; Cationic Trypsinogen; Variants; Prss1-prss2; Gene; Inhibitor; Mutation
ISSN (print) / ISBN 0017-5749
e-ISSN 1468-3288
Journal Gut (eGut)
Quellenangaben Volume: 67, Issue: 10, Pages: 1855–186 Article Number: , Supplement: ,
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Genomics (CF-GEN)
Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)