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Rosendahl, Jonas; Kirsten, Holger; Hegyi, Eszter; Kovacs, Peter; Weiss, Frank Ulrich; Laumen, Helmut; Lichtner, Peter; Ruffert, Claudia; Chen, Jian-Min; Masson, Emmanuelle; Beer, Sebastian; Zimmer, Constantin; Seltsam, Katharina; Algül, Hana; Bühler, Florence; Bruno, Marco J; Bugert, Peter; Burkhardt, Ralph; Cavestro, Giulia Martina; Cichoz-Lach, Halina; Farré, Antoni; Frank, Josef; Gambaro, Giovanni; Gimpfl, Sebastian; [...]

Genome-wide association study identifies inversion in theCTRB1-CTRB2locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

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  • Media type: E-Article
  • Title: Genome-wide association study identifies inversion in theCTRB1-CTRB2locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
  • Contributor: Rosendahl, Jonas; Kirsten, Holger; Hegyi, Eszter; Kovacs, Peter; Weiss, Frank Ulrich; Laumen, Helmut; Lichtner, Peter; Ruffert, Claudia; Chen, Jian-Min; Masson, Emmanuelle; Beer, Sebastian; Zimmer, Constantin; Seltsam, Katharina; Algül, Hana; Bühler, Florence; Bruno, Marco J; Bugert, Peter; Burkhardt, Ralph; Cavestro, Giulia Martina; Cichoz-Lach, Halina; Farré, Antoni; Frank, Josef; Gambaro, Giovanni; Gimpfl, Sebastian; [...]
  • Published: BMJ, 2018
  • Published in: Gut, 67 (2018) 10, Seite 1855-1863
  • Language: English
  • DOI: 10.1136/gutjnl-2017-314454
  • ISSN: 0017-5749; 1468-3288
  • Origination:
  • Footnote:
  • Description: ObjectiveAlcohol-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.Design1959 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.ResultsWe replicated previously reported risk lociCLDN2-MORC4,CTRC,PRSS1-PRSS2andSPINK1in alcoholic CP patients. We identifiedCTRB1-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 theCTRB1-CTRB2locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged byrs8048956. 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.ConclusionAn inversion in theCTRB1-CTRB2locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.