Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
Authors: Alberts Rudi , de Vries Elisabeth M G , Goode Elizabeth C , Jiang Xiaojun , Sampaziotis Fotis , Rombouts Krista , Böttcher Katrin , Folseraas Trine , Weismüller Tobias J , Mason Andrew L , Wang Weiwei , Alexander Graeme , Alvaro Domenico , Bergquist Annika , Björkström Niklas K , Beuers Ulrich , Björnsson Einar , Boberg Kirsten Muri , Bowlus Christopher L , Bragazzi Maria C , Carbone Marco , Chazouillères Olivier , Cheung Angela , Dalekos Georgios , Eaton John , Eksteen Bertus , Ellinghaus David , Färkkilä Martti , Festen Eleonora A M , Floreani Annarosa , Franceschet Irene , Gotthardt Daniel Nils , Hirschfield Gideon M , Hoek Bart van , Holm Kristian , Hohenester Simon , Hov Johannes Roksund , Imhann Floris , Invernizzi Pietro , Juran Brian D , Lenzen Henrike , Lieb Wolfgang , Liu Jimmy Z , Marschall Hanns-Ulrich , Marzioni Marco , Melum Espen , Milkiewicz Piotr , Müller Tobias , Pares Albert , Rupp Christian , Rust Christian , Sandford Richard N , Schramm Christoph , Schreiber Stefan , Schrumpf Erik , Silverberg Mark S , Srivastava Brijesh , Sterneck Martina , Teufel Andreas , Vallier Ludovic , Verheij Joanne , Vila Arnau Vich , Vries Boudewijn de , Zachou Kalliopi , Chapman Roger W , Manns Michael P , Pinzani Massimo , Rushbrook Simon M , Lazaridis Konstantinos N , Franke Andre , Anderson Carl A , Karlsen Tom H , Ponsioen Cyriel Y , Weersma Rinse K 
Published: August 2017

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 geneRSPO3in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.