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RESEARCH PRODUCT
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
Martina SterneckWolfgang LiebChristian RustTom H. KarlsenMassimo PinzaniErik SchrumpfJohn E. EatonGideon M. HirschfieldChristoph SchrammRichard SandfordUlrich BeuersAndrew MasonEspen MelumDaniel GotthardtA. Boudewijn De VriesI. FranceschetKonstantinos N. LazaridisFloris ImhannMarco CarbonePietro InvernizziMark S. SilverbergSimon HohenesterMaria Consiglia BragazziAndreas TeufelBart Van HoekMartti FärkkiläEinar BjornssonCyriel Y. PonsioenBrijesh SrivastavaJoanne VerheijRoger W. ChapmanKrista RomboutsNiklas K. BjörkströmJohannes R. HovWeiwei WangF. SampaziotisLudovic VallierLudovic VallierAlbert ParésEleonora A. M. FestenKristian HolmKalliopi ZachouKatrin BöttcherChristopher L. BowlusXiaojun JiangTrine FolseraasElisabeth M.g. De VriesSimon M. RushbrookPiotr MilkiewiczCarl A. AndersonGeorgios N. DalekosDavid EllinghausHanns-ulrich MarschallRinse K. WeersmaMarco MarzioniOlivier ChazouillèresDomenico AlvaroChristian RuppAngela M. CheungJimmy Z. LiuBrian D. JuranMichael P. MannsRudi AlbertsBertus EksteenTobias J. WeismüllerGraeme J.m. AlexanderAnnarosa FloreaniTobias MüllerStefan SchreiberAndre FrankeElizabeth C. GoodeElizabeth C. GoodeHenrike LenzenArnau Vich VilaAnnika BergquistKirsten Muri BobergKirsten Muri Bobergsubject
Male0301 basic medicineOncologyCandidate geneCholangitismedicine.medical_treatmentMedizinTrasplantament hepàticGenome-wide association studyKaplan-Meier EstimateLIVER FIBROSISLiver transplantationBioinformaticsSclerosingOral and gastrointestinalPrimary sclerosing cholangitis; genetics; liver transplantationCohort StudiesACTIVATION0302 clinical medicineMED/12 - GASTROENTEROLOGIAMULTIPLE2.1 Biological and endogenous factorsEPIDEMIOLOGYgeneticsAetiologyCIRRHOSISliver transplantationBilious diseases and biliousnessPrimary sclerosing cholangitisLiver Diseasedigestive oral and skin physiologyGastroenterologySingle NucleotidePrimary sclerosing cholangitiMiddle Aged3. Good healthULCERATIVE-COLITISDisease ProgressionFemale030211 gastroenterology & hepatologyAdultmedicine.medical_specialtyCholangitis SclerosingChronic Liver Disease and CirrhosisClinical SciencesMalalties del tracte biliarSingle-nucleotide polymorphismHEPATIC STELLATE CELLSPolymorphism Single NucleotideInternational PSC Study GroupArticlePrimary sclerosing cholangitisPaediatrics and Reproductive Medicine03 medical and health sciencesRare DiseasesClinical ResearchInternal medicineGeneticsmedicineHumansPolymorphismGENOME-WIDE ASSOCIATIONAlleleDigestive Diseases - (Gallbladder)Survival analysisProportional Hazards ModelsMALIGNANCYThe UK PSC ConsortiumTransplantationGastroenterology & Hepatologybusiness.industryProportional hazards modelmedicine.diseaseRISK LOCILogistic Models030104 developmental biology3121 General medicine internal medicine and other clinical medicinegeneticHepatic transplantationThrombospondinsDigestive DiseasesbusinessGenèticadescription
ObjectivePrimary 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.DesignWe 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.ResultsWe 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.ConclusionWe 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-08-01 | Gut |