BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. METHODS: We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. RESULTS: The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10⁻⁶, OR(A vs G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10⁻⁴, OR(A vs G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10⁻⁴, OR(A vs T) = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P (combined) = 3.8 × 10⁻¹²) and rs4147359 (10p15 (IL2RA), P (combined) = 1.5 × 10⁻⁸). CONCLUSION: We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.
BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. METHODS: We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. RESULTS: The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10⁻⁶, OR(A vs G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10⁻⁴, OR(A vs G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10⁻⁴, OR(A vs T) = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P (combined) = 3.8 × 10⁻¹²) and rs4147359 (10p15 (IL2RA), P (combined) = 1.5 × 10⁻⁸). CONCLUSION: We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.
Authors: Steven E Kauder; Lydia Santell; Elaine Mai; Lilyan Y Wright; Elizabeth Luis; Elsa N N'Diaye; Jeff Lutman; Navneet Ratti; Susan M Sa; Henry R Maun; Eric Stefanich; Lino C Gonzalez; Robert R Graham; Lauri Diehl; William A Faubion; Mary E Keir; Judy Young; Amitabha Chaudhuri; Robert A Lazarus; Jackson G Egen Journal: PLoS One Date: 2013-12-23 Impact factor: 3.240
Authors: Sun-Gou Ji; Brian D Juran; Sören Mucha; Trine Folseraas; Luke Jostins; Espen Melum; Natsuhiko Kumasaka; Elizabeth J Atkinson; Erik M Schlicht; Jimmy Z Liu; Tejas Shah; Javier Gutierrez-Achury; Kirsten M Boberg; Annika Bergquist; Severine Vermeire; Bertus Eksteen; Peter R Durie; Martti Farkkila; Tobias Müller; Christoph Schramm; Martina Sterneck; Tobias J Weismüller; Daniel N Gotthardt; David Ellinghaus; Felix Braun; Andreas Teufel; Mattias Laudes; Wolfgang Lieb; Gunnar Jacobs; Ulrich Beuers; Rinse K Weersma; Cisca Wijmenga; Hanns-Ulrich Marschall; Piotr Milkiewicz; Albert Pares; Kimmo Kontula; Olivier Chazouillères; Pietro Invernizzi; Elizabeth Goode; Kelly Spiess; Carmel Moore; Jennifer Sambrook; Willem H Ouwehand; David J Roberts; John Danesh; Annarosa Floreani; Aliya F Gulamhusein; John E Eaton; Stefan Schreiber; Catalina Coltescu; Christopher L Bowlus; Velimir A Luketic; Joseph A Odin; Kapil B Chopra; Kris V Kowdley; Naga Chalasani; Michael P Manns; Brijesh Srivastava; George Mells; Richard N Sandford; Graeme Alexander; Daniel J Gaffney; Roger W Chapman; Gideon M Hirschfield; Mariza de Andrade; Simon M Rushbrook; Andre Franke; Tom H Karlsen; Konstantinos N Lazaridis; Carl A Anderson Journal: Nat Genet Date: 2016-12-19 Impact factor: 38.330
Authors: Jimmy Z Liu; Johannes Roksund Hov; Trine Folseraas; Eva Ellinghaus; Simon M Rushbrook; Nadezhda T Doncheva; Ole A Andreassen; Rinse K Weersma; Tobias J Weismüller; Bertus Eksteen; Pietro Invernizzi; Gideon M Hirschfield; Daniel Nils Gotthardt; Albert Pares; David Ellinghaus; Tejas Shah; Brian D Juran; Piotr Milkiewicz; Christian Rust; Christoph Schramm; Tobias Müller; Brijesh Srivastava; Georgios Dalekos; Markus M Nöthen; Stefan Herms; Juliane Winkelmann; Mitja Mitrovic; Felix Braun; Cyriel Y Ponsioen; Peter J P Croucher; Martina Sterneck; Andreas Teufel; Andrew L Mason; Janna Saarela; Virpi Leppa; Ruslan Dorfman; Domenico Alvaro; Annarosa Floreani; Suna Onengut-Gumuscu; Stephen S Rich; Wesley K Thompson; Andrew J Schork; Sigrid Næss; Ingo Thomsen; Gabriele Mayr; Inke R König; Kristian Hveem; Isabelle Cleynen; Javier Gutierrez-Achury; Isis Ricaño-Ponce; David van Heel; Einar Björnsson; Richard N Sandford; Peter R Durie; Espen Melum; Morten H Vatn; Mark S Silverberg; Richard H Duerr; Leonid Padyukov; Stephan Brand; Miquel Sans; Vito Annese; Jean-Paul Achkar; Kirsten Muri Boberg; Hanns-Ulrich Marschall; Olivier Chazouillères; Christopher L Bowlus; Cisca Wijmenga; Erik Schrumpf; Severine Vermeire; Mario Albrecht; John D Rioux; Graeme Alexander; Annika Bergquist; Judy Cho; Stefan Schreiber; Michael P Manns; Martti Färkkilä; Anders M Dale; Roger W Chapman; Konstantinos N Lazaridis; Andre Franke; Carl A Anderson; Tom H Karlsen Journal: Nat Genet Date: 2013-04-21 Impact factor: 38.330