Genome-wide association study identifies inversion in the
CTRB1-CTRB2
locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
Authors: 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 , Grallert Harald , Griesmann Heidi , Grützmann Robert , Hellerbrand Claus , Hegyi Péter , Hollenbach Marcus , Iordache Sevastitia , Jurkowska Grazyna , Keim Volker , Kiefer Falk , Krug Sebastian , Landt Olfert , Leo Milena Di , Lerch Markus M , Lévy Philippe , Löffler Markus , Löhr Matthias , Ludwig Maren , Macek Milan , Malats Nuria , Malecka-Panas Ewa , Malerba Giovanni , Mann Karl , Mayerle Julia , Mohr Sonja , te Morsche Rene H M , Motyka Marie , Mueller Sebastian , Müller Thomas , Nöthen Markus M , Pedrazzoli Sergio , Pereira Stephen P , Peters Annette , Pfützer Roland , Real Francisco X , Rebours Vinciane , Ridinger Monika , Rietschel Marcella , Rösmann Eva , Saftoiu Adrian , Schneider Alexander , Schulz Hans-Ulrich , Soranzo Nicole , Soyka Michael , Simon Peter , Skipworth James , Stickel Felix , Strauch Konstantin , Stumvoll Michael , Testoni Pier Alberto , Tönjes Anke , Werner Lena , Werner Jens , Wodarz Norbert , Ziegler Martin , Masamune Atsushi , Mössner Joachim , Férec Claude , Michl Patrick , P H Drenth Joost , Witt Heiko , Scholz Markus , Sahin-Tóth Miklós 
Published: July 2017

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.