RT Journal Article
SR Electronic
T1 Genome-wide association study identifies inversion in the <em>CTRB1-CTRB2</em> locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1855
OP 1863
DO 10.1136/gutjnl-2017-314454
VO 67
IS 10
A1 Jonas Rosendahl
A1 Holger Kirsten
A1 Eszter Hegyi
A1 Peter Kovacs
A1 Frank Ulrich Weiss
A1 Helmut Laumen
A1 Peter Lichtner
A1 Claudia Ruffert
A1 Jian-Min Chen
A1 Emmanuelle Masson
A1 Sebastian Beer
A1 Constantin Zimmer
A1 Katharina Seltsam
A1 Hana Algül
A1 Florence Bühler
A1 Marco J Bruno
A1 Peter Bugert
A1 Ralph Burkhardt
A1 Giulia Martina Cavestro
A1 Halina Cichoz-Lach
A1 Antoni Farré
A1 Josef Frank
A1 Giovanni Gambaro
A1 Sebastian Gimpfl
A1 Harald Grallert
A1 Heidi Griesmann
A1 Robert Grützmann
A1 Claus Hellerbrand
A1 Péter Hegyi
A1 Marcus Hollenbach
A1 Sevastitia Iordache
A1 Grazyna Jurkowska
A1 Volker Keim
A1 Falk Kiefer
A1 Sebastian Krug
A1 Olfert Landt
A1 Milena Di Leo
A1 Markus M Lerch
A1 Philippe Lévy
A1 Markus Löffler
A1 Matthias Löhr
A1 Maren Ludwig
A1 Milan Macek
A1 Nuria Malats
A1 Ewa Malecka-Panas
A1 Giovanni Malerba
A1 Karl Mann
A1 Julia Mayerle
A1 Sonja Mohr
A1 Rene H M te Morsche
A1 Marie Motyka
A1 Sebastian Mueller
A1 Thomas Müller
A1 Markus M Nöthen
A1 Sergio Pedrazzoli
A1 Stephen P Pereira
A1 Annette Peters
A1 Roland Pfützer
A1 Francisco X Real
A1 Vinciane Rebours
A1 Monika Ridinger
A1 Marcella Rietschel
A1 Eva Rösmann
A1 Adrian Saftoiu
A1 Alexander Schneider
A1 Hans-Ulrich Schulz
A1 Nicole Soranzo
A1 Michael Soyka
A1 Peter Simon
A1 James Skipworth
A1 Felix Stickel
A1 Konstantin Strauch
A1 Michael Stumvoll
A1 Pier Alberto Testoni
A1 Anke Tönjes
A1 Lena Werner
A1 Jens Werner
A1 Norbert Wodarz
A1 Martin Ziegler
A1 Atsushi Masamune
A1 Joachim Mössner
A1 Claude Férec
A1 Patrick Michl
A1 Joost P H Drenth
A1 Heiko Witt
A1 Markus Scholz
A1 Miklós Sahin-Tóth
A1 ,
YR 2018
UL http://gut.bmj.com/content/67/10/1855.abstract
AB 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.