Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Tobias Müller, Rudi Alberts, Elisabeth M. G. de Vries, Elizabeth C. Goode, Xiaojun Jiang, Fotis Sampaziotis, Krista Rombouts, Katrin Böttcher, Trine Folseraas, Tobias J. Weismüller, Andrew L. Mason, Weiwei Wang, Graeme Alexander, Domenico Alvaro, Annika Bergquist, Niklas K. Björkström, Ulrich Beuers, Einar Björnsson, Kirsten Muri Boberg, Christopher L. BowlusMaria C. Bragazzi, Marco Carbone, Olivier Chazouillères, Angela Cheung, Georgios Dalekos, John Eaton, Bertus Eksteen, David Ellinghaus, Martti Färkkilä, Eleonora A. M. Festen, Annarosa Floreani, Irene Franceschet, Daniel Nils Gotthardt, Gideon M. Hirschfield, Bart Van Hoek, Kristian Holm, Simon Hohenester, Johannes Roksund Hov, Floris Imhann, Pietro Invernizzi, Brian D. Juran, Henrike Lenzen, Wolfgang Lieb, Jimmy Z. Liu, Hanns-Ulrich Marschall, Marco Marzioni, Espen Melum, Piotr Milkiewicz, Albert Pares, Christian Rupp, Christian Rust, Richard N. Sandford, Christoph Schramm, Stefan Schreiber, Erik Schrumpf, Mark S. Silverberg, Brijesh Srivastava, Martina Sterneck, Andreas Teufel, Ludovic Vallier, Joanne Verheij, Arnau Vich Vila, Boudewijn de Vries, Kalliopi Zachou, Roger W. Chapman, Michael P. Manns, Massimo Pinzani, Simon M. Rushbrook, Konstantinos N. Lazaridis, Andre Franke, Carl A. Anderson, Tom H. Karlsen, Cyriel Y. Ponsioen, Rinse K. Weersma, Boukje de Vries

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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.
Original languageEnglish
Pages (from-to)1517-1524
Issue number8
Publication statusPublished - 2018

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