TY - JOUR T1 - Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis JF - Gut JO - Gut SP - 1517 LP - 1524 DO - 10.1136/gutjnl-2016-313598 VL - 67 IS - 8 AU - Rudi Alberts AU - Elisabeth M G de Vries AU - Elizabeth C Goode AU - Xiaojun Jiang AU - Fotis Sampaziotis AU - Krista Rombouts AU - Katrin Böttcher AU - Trine Folseraas AU - Tobias J Weismüller AU - Andrew L Mason AU - Weiwei Wang AU - Graeme Alexander AU - Domenico Alvaro AU - Annika Bergquist AU - Niklas K Björkström AU - Ulrich Beuers AU - Einar Björnsson AU - Kirsten Muri Boberg AU - Christopher L Bowlus AU - Maria C Bragazzi AU - Marco Carbone AU - Olivier Chazouillères AU - Angela Cheung AU - Georgios Dalekos AU - John Eaton AU - Bertus Eksteen AU - David Ellinghaus AU - Martti Färkkilä AU - Eleonora A M Festen AU - Annarosa Floreani AU - Irene Franceschet AU - Daniel Nils Gotthardt AU - Gideon M Hirschfield AU - Bart van Hoek AU - Kristian Holm AU - Simon Hohenester AU - Johannes Roksund Hov AU - Floris Imhann AU - Pietro Invernizzi AU - Brian D Juran AU - Henrike Lenzen AU - Wolfgang Lieb AU - Jimmy Z Liu AU - Hanns-Ulrich Marschall AU - Marco Marzioni AU - Espen Melum AU - Piotr Milkiewicz AU - Tobias Müller AU - Albert Pares AU - Christian Rupp AU - Christian Rust AU - Richard N Sandford AU - Christoph Schramm AU - Stefan Schreiber AU - Erik Schrumpf AU - Mark S Silverberg AU - Brijesh Srivastava AU - Martina Sterneck AU - Andreas Teufel AU - Ludovic Vallier AU - Joanne Verheij AU - Arnau Vich Vila AU - Boudewijn de Vries AU - Kalliopi Zachou AU - The International PSC Study Group, The UK PSC Consortium AU - Roger W Chapman AU - Michael P Manns AU - Massimo Pinzani AU - Simon M Rushbrook AU - Konstantinos N Lazaridis AU - Andre Franke AU - Carl A Anderson AU - Tom H Karlsen AU - Cyriel Y Ponsioen AU - Rinse K Weersma Y1 - 2018/08/01 UR - http://gut.bmj.com/content/67/8/1517.abstract N2 - Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene. ER -