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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)1517-1524
Number of pages8
JournalGut
Volume67
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Sclerosing Cholangitis
Disease Progression
Liver
Transplants
Survival
Bile Duct Diseases
Modifier Genes
Hepatic Stellate Cells
Genetic Loci
Kaplan-Meier Estimate
Survival Analysis
Proportional Hazards Models
Quality Control
Liver Transplantation
Single Nucleotide Polymorphism
Logistic Models
Alleles
Genome
Gene Expression

Keywords

  • genetics
  • liver transplantation
  • Primary sclerosing cholangitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Müller, T., Alberts, R., De Vries, E. M. G., Goode, E. C., Jiang, X., Sampaziotis, F., ... Weersma, R. K. (2018). Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut, 67(8), 1517-1524. https://doi.org/10.1136/gutjnl-2016-313598

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. / Müller, Tobias; 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; 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; De Vries, Boudewijn; 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.

In: Gut, Vol. 67, No. 8, 01.08.2018, p. 1517-1524.

Research output: Contribution to journalArticle

Müller, T, Alberts, R, De Vries, EMG, Goode, EC, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, TJ, Mason, AL, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, NK, Beuers, U, Björnsson, E, Boberg, KM, Bowlus, CL, Bragazzi, MC, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, EAM, Floreani, A, Franceschet, I, Gotthardt, DN, Hirschfield, GM, Hoek, BV, Holm, K, Hohenester, S, Hov, JR, Imhann, F, Invernizzi, P, Juran, BD, Lenzen, H, Lieb, W, Liu, JZ, Marschall, HU, Marzioni, M, Melum, E, Milkiewicz, P, Pares, A, Rupp, C, Rust, C, Sandford, RN, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, MS, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, AV, De Vries, B, Zachou, K, Chapman, RW, Manns, MP, Pinzani, M, Rushbrook, SM, Lazaridis, KN, Franke, A, Anderson, CA, Karlsen, TH, Ponsioen, CY & Weersma, RK 2018, 'Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis', Gut, vol. 67, no. 8, pp. 1517-1524. https://doi.org/10.1136/gutjnl-2016-313598
Müller, Tobias ; 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 ; 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 ; De Vries, Boudewijn ; 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. / Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. In: Gut. 2018 ; Vol. 67, No. 8. pp. 1517-1524.
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title = "Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis",
abstract = "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.",
keywords = "genetics, liver transplantation, Primary sclerosing cholangitis",
author = "Tobias M{\"u}ller and Rudi Alberts and {De Vries}, {Elisabeth M.G.} and Goode, {Elizabeth C.} and Xiaojun Jiang and Fotis Sampaziotis and Krista Rombouts and Katrin B{\"o}ttcher and Trine Folseraas and Weism{\"u}ller, {Tobias J.} and Mason, {Andrew L.} and Weiwei Wang and Graeme Alexander and Domenico Alvaro and Annika Bergquist and Bj{\"o}rkstr{\"o}m, {Niklas K.} and Ulrich Beuers and Einar Bj{\"o}rnsson and Boberg, {Kirsten Muri} and Bowlus, {Christopher L.} and Bragazzi, {Maria C.} and Marco Carbone and Olivier Chazouill{\`e}res and Angela Cheung and Georgios Dalekos and John Eaton and Bertus Eksteen and David Ellinghaus and Martti F{\"a}rkkil{\"a} and Festen, {Eleonora A.M.} and Annarosa Floreani and Irene Franceschet and Gotthardt, {Daniel Nils} and Hirschfield, {Gideon M.} and Hoek, {Bart Van} and Kristian Holm and Simon Hohenester and Hov, {Johannes Roksund} and Floris Imhann and Pietro Invernizzi and Juran, {Brian D.} and Henrike Lenzen and Wolfgang Lieb and Liu, {Jimmy Z.} and Marschall, {Hanns Ulrich} and Marco Marzioni and Espen Melum and Piotr Milkiewicz and Albert Pares and Christian Rupp and Christian Rust and Sandford, {Richard N.} and Christoph Schramm and Stefan Schreiber and Erik Schrumpf and Silverberg, {Mark S.} and Brijesh Srivastava and Martina Sterneck and Andreas Teufel and Ludovic Vallier and Joanne Verheij and Vila, {Arnau Vich} and {De Vries}, Boudewijn and Kalliopi Zachou and Chapman, {Roger W.} and Manns, {Michael P.} and Massimo Pinzani and Rushbrook, {Simon M.} and Lazaridis, {Konstantinos N} and Andre Franke and Anderson, {Carl A.} and Karlsen, {Tom H.} and Ponsioen, {Cyriel Y.} and Weersma, {Rinse K.}",
year = "2018",
month = "8",
day = "1",
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pages = "1517--1524",
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TY - JOUR

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

AU - Müller, Tobias

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 - 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 - De Vries, Boudewijn

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.

PY - 2018/8/1

Y1 - 2018/8/1

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.

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 gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

KW - genetics

KW - liver transplantation

KW - Primary sclerosing cholangitis

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U2 - 10.1136/gutjnl-2016-313598

DO - 10.1136/gutjnl-2016-313598

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C2 - 28779025

AN - SCOPUS:85033337166

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JO - Gut

JF - Gut

SN - 0017-5749

IS - 8

ER -