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

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 id...

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Autores: Parés Darnaculleta, Albert, Vich Vila, Arnau, Goode, Elizabeth C., Srivastava, Brijesh, Alvaro, Domenico, Franceschet, Irene, The UK PSC Consortium, The International PSC Study Group
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/137820
Acceso en línea:https://hdl.handle.net/2445/137820
Access Level:acceso abierto
Palabra clave:Malalties del tracte biliar
Genètica
Trasplantament hepàtic
Bilious diseases and biliousness
Genetics
Hepatic transplantation
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spelling Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitisParés Darnaculleta, AlbertVich Vila, ArnauGoode, Elizabeth C.Srivastava, BrijeshAlvaro, DomenicoFranceschet, IreneThe UK PSC ConsortiumThe International PSC Study GroupMalalties del tracte biliarGenèticaTrasplantament hepàticBilious diseases and biliousnessGeneticsHepatic transplantationOBJECTIVE: 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.BMJ Publishing Group2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/137820Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2016-313598Gut, 2017, vol. 67, num. 8, p. 1517-1524https://doi.org/10.1136/gutjnl-2016-313598(c) Parés Darnaculleta, Albert et al., 2017info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1378202026-05-27T06:46:51Z
dc.title.none.fl_str_mv Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
title Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
spellingShingle Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
Parés Darnaculleta, Albert
Malalties del tracte biliar
Genètica
Trasplantament hepàtic
Bilious diseases and biliousness
Genetics
Hepatic transplantation
title_short Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
title_full Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
title_fullStr Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
title_full_unstemmed Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
title_sort Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
dc.creator.none.fl_str_mv Parés Darnaculleta, Albert
Vich Vila, Arnau
Goode, Elizabeth C.
Srivastava, Brijesh
Alvaro, Domenico
Franceschet, Irene
The UK PSC Consortium
The International PSC Study Group
author Parés Darnaculleta, Albert
author_facet Parés Darnaculleta, Albert
Vich Vila, Arnau
Goode, Elizabeth C.
Srivastava, Brijesh
Alvaro, Domenico
Franceschet, Irene
The UK PSC Consortium
The International PSC Study Group
author_role author
author2 Vich Vila, Arnau
Goode, Elizabeth C.
Srivastava, Brijesh
Alvaro, Domenico
Franceschet, Irene
The UK PSC Consortium
The International PSC Study Group
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties del tracte biliar
Genètica
Trasplantament hepàtic
Bilious diseases and biliousness
Genetics
Hepatic transplantation
topic Malalties del tracte biliar
Genètica
Trasplantament hepàtic
Bilious diseases and biliousness
Genetics
Hepatic transplantation
description 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.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/137820
url https://hdl.handle.net/2445/137820
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2016-313598
Gut, 2017, vol. 67, num. 8, p. 1517-1524
https://doi.org/10.1136/gutjnl-2016-313598
dc.rights.none.fl_str_mv (c) Parés Darnaculleta, Albert et al., 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Parés Darnaculleta, Albert et al., 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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