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.
- Primary sclerosing cholangitis
- liver transplantation
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RA and EMGV contributed equally.
Contributors RA, EMGdV, XJ, FS, KR, KS, ALM and WW: statistical analysis and interpretation of data. CYP and RKW: study supervision. KR, KS, XJ, FS and MP: performed experiments. RA, EMGdV, THK, SH, CS, TF, JRH, EM, FS, CYP and RKW wrote the manuscript. JZL, AFranke, DE and CAA performed genotyping, calling and QC. RA, EMGdV, ECG, XJ, FS, KR, KS, TF, TJW, ALM, WW, GA, DA, AB, NKB, UB,EB, KMB, CLB, MCB, MC, OC, AC, GD, JE, BE, DE, MF, EAMF, AFloreani, IF, DNG,GMH, BvH, KH, SH, JRH, FI, PI,BDJ, HL,WL, JZL, H-UM, MM, EM, PM, TM, AP, CRupp,CRust, RNS, CS, SS, ES, MSilverberg, BS, MSterneck, AT, LV, JV, AVV, BdV, KZ,RWC, MPM, MP, SMR, KNL, AFranke, CAA, THK, CYP, RKW, The UK–PSC Consortium and The International PSC Study Group contributed to sample and clinical data collection. All authors revised the manuscript for critical content and approved the finalversion.
Funding RA is supported by a PSC Partners Seeking a Cure grant ‘Unraveling genetics driving PSC subphenotypes: anIPSCSG study’. LV and FS are supported by the ERC grant Relieve IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Center. SH is supported by a grant from the German Research Community (DFG), grant HO 4460/2–1. TM is supported by the German Research Community (DFG), grants MU 2864/1–1 and MU 2864/1–3. KNL is supported by the NIH RO1 DK 084960 and Sigismunda Palumbo Charitable Trust. EAMF is supported by a Career Development Grant from Dutch Digestive Foundation (Maag Lever Darm Stichting, MLDS). RKW is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and a PSC Partners Seeking a Cure grant ‘The Exome in PSC’.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Subject recruitment was approved by the ethics committees or institutional review boards of all participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.
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