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.
OC-030 Effective Stratification Of Hepatocellular Carcinoma Risk In Primary Biliary Cirrhosis: Results Of A Multi-centre International Study
Trivedi, PJ, Buuren, H. van, Battezzati, Pm, Floreani, Annarosa , Ponsioen, Cyriel Y. , Poupon, R., Mayo, Marlyn J. , Talwalkar, Jayant A., Burroughs, AK, Nevens, Frederik , Bruns, Tony , Li, KK, Cheung, Angela , Cazagon, N, Franceschet, I., Imam, Mohamad , Pieri, Giulia , Kanwar, Pushpjeet, Lindor, Keith D. , Lammers, Willem J. , Janssen, Harry L.A. , Invernizzi, Pietro , Parés, Albert , Corpechot, Christophe , Mason, Andrew L. , Kowdley, Kris V. , Kumagi, Teru , Lleò, Ana , Caballería, Llorenç , Boonstra, Kirsten , Vries, Esther de , Hansen, Bettina E. , Hirschfield, Gideon M. , Bruns, Tony
Gut | June 9, 2014 | Volume: 63 | Issue: Suppl 1 | Pages: A15-A16
Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.