Citations 2
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
Alberts, Rudi , Vries, Elisabeth M. G. de, Goode, Elizabeth C. , Jiang, Xiaojun , Sampaziotis, Fotis , Rombouts, Krista , Böttcher, Katrin , Folseraas, Trine , Weismüller, Tobias J. , Alexander, Graeme, Alvaro, Domenico , Bergquist, Annika , Björkström, Niklas K. , Beuers, Ulrich , Boberg, Kirsten Muri , Bowlus, Christopher L. , Bragazzi, Maria Consiglia , Chazouillères, Olivier , Cheung, Angela , Dalekos, Georgios, Eaton, John E. , Eksteen, Bertus , Ellinghaus, David , Färkkilâ, Martti , Festen, Eleonora A. , Floreani, Annarosa , Franceschet, I., Gotthardt, Daniel , Hoek, Bart van , Holm, Kristian , Hov, Johannes R. , Imhann, Floris , Juran, Brian D., Lenzen, Henrike , Marschall, Hanns–Ulrich , Marzioni, Marco , Melum, Espen , Milkiewicz, Piotr , Müller, Tobias , Parés, Albert , Rupp, Christian , Rust, Christian, Sandford, Richard , Schrumpf, Erik, Silverberg, Mark S. , Srivastava, Brijesh, Sterneck, Martina , Teufel, Andreas , Vallier, Ludovic , Verheij, Joanne , Vila, Arnau Vich , Vries, Boudewijn de, Zachou, Kalliopi , Chapman, Roger W. , Manns, Michael P. , Rushbrook, Simon, Anderson, Carl A. , Karlsen, Tom H. , Ponsioen, Cyriel Y. , Weersma, Rinse K. , Eaton, John, Lazaridis, Konstantinos N. , Ellinghaus, David , Bowlus, Christopher L , Marzioni, Marco , Mason, Andrew L. , Wang, Weiwei , Bjornsson, Einar Stefan , Carbone, Marco , Dalekos, Georgios, Hirschfield, Gideon M. , Hohenester, Simon D. , Invernizzi, Pietro , Lieb, Wolfgang , Liu, Jimmy Z. , Schramm, Christoph , Schreiber, Stefan , Pinzani, Massimo , Franke, André , Bergquist, Annika , Milkiewicz, Piotr , Alvaro, Domenico , Hov, Johannes R , Anderson, Carl A
Gut | August 4, 2017 | Volume: 67 | Issue: 8 | Pages: 1517-1524
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.
Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process
Ponsioen, Cyriel Y. , Chapman, Roger W. , Chazouillères, Olivier , Hirschfield, Gideon M. , Karlsen, Tom H. , Lohse, Ansgar W. , Schrumpf, Erik, Trauner, Michael , Pinzani, Massimo , Gores, Gregory J. , Hirschfield, Gideon M
Hepatology | September 29, 2015 | Volume: 63 | Issue: 4 | Pages: 1357-1367
Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end‐stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. Conclusion: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. (Hepatology 2016;63:1357–1367)