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

TY - JOUR

T1 - Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

AU - Alberts, Rudi

AU - de Vries, Elisabeth M G

AU - Goode, Elizabeth C

AU - Jiang, Xiaojun

AU - Sampaziotis, Fotis

AU - Rombouts, Krista

AU - Böttcher, Katrin

AU - Folseraas, Trine

AU - Weismüller, Tobias J

AU - Mason, Andrew L

AU - Wang, Weiwei

AU - Alexander, Graeme

AU - Alvaro, Domenico

AU - Bergquist, Annika

AU - Björkström, Niklas K

AU - Beuers, Ulrich

AU - Björnsson, Einar

AU - Boberg, Kirsten Muri

AU - Bowlus, Christopher L

AU - Bragazzi, Maria C

AU - Carbone, Marco

AU - Chazouillères, Olivier

AU - Cheung, Angela

AU - Dalekos, Georgios

AU - Eaton, John

AU - Eksteen, Bertus

AU - Ellinghaus, David

AU - Färkkilä, Martti

AU - Festen, Eleonora A M

AU - Floreani, Annarosa

AU - Franceschet, Irene

AU - Gotthardt, Daniel Nils

AU - Hirschfield, Gideon M

AU - Hoek, Bart van

AU - Holm, Kristian

AU - Hohenester, Simon

AU - Hov, Johannes Roksund

AU - Imhann, Floris

AU - Invernizzi, Pietro

AU - Juran, Brian D

AU - Lenzen, Henrike

AU - Lieb, Wolfgang

AU - Liu, Jimmy Z

AU - Marschall, Hanns-Ulrich

AU - Marzioni, Marco

AU - Melum, Espen

AU - Milkiewicz, Piotr

AU - Müller, Tobias

AU - Pares, Albert

AU - Rupp, Christian

AU - Rust, Christian

AU - Sandford, Richard N

AU - Schramm, Christoph

AU - Schreiber, Stefan

AU - Schrumpf, Erik

AU - Silverberg, Mark S

AU - Srivastava, Brijesh

AU - Sterneck, Martina

AU - Teufel, Andreas

AU - Vallier, Ludovic

AU - Verheij, Joanne

AU - Vila, Arnau Vich

AU - Vries, Boudewijn de

AU - Zachou, Kalliopi

AU - Chapman, Roger W

AU - Manns, Michael P

AU - Pinzani, Massimo

AU - Rushbrook, Simon M

AU - Lazaridis, Konstantinos N

AU - Franke, Andre

AU - Anderson, Carl A

AU - Karlsen, Tom H

AU - Ponsioen, Cyriel Y

AU - Weersma, Rinse K

AU - International PSC Study Group, The UK PSC Consortium

N1 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

PY - 2018/8

Y1 - 2018/8

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

AB - 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.

KW - Journal Article

U2 - 10.1136/gutjnl-2016-313598

DO - 10.1136/gutjnl-2016-313598

M3 - SCORING: Journal article

C2 - 28779025

VL - 67

SP - 1517

EP - 1524

JO - GUT

JF - GUT

SN - 0017-5749

IS - 8

ER -