Genome-Wide Association Analysis in Primary Sclerosing Cholangitis And Ulcerative Colitis Identifies Risk Loci at Gpr35 And Tcf4

作者：David Ellinghaus, Trine Folseraas, Kristian Holm, Eva Ellinghaus, Espen Melum, Tobias C. Balschun, Jon K. Laerdahl, Alexey Shiryaev, Daniel Nils Gotthardt, Tobias J. Weismüller, Christoph Schramm, Michael Wittig, Annika M Bergquist, Einar Stefan Bjornsson, Hanns–Ulrich Marschall, Morten Vatn, Andreas Teufel, Christian Rust, Christian Gieger, H‐Erich Wichmann, Heiko Runz, Martina R. Sterneck, Christian Rupp, Felix Braun, Rinse Karel Weersma, Cisca Wijmenga, Cyriel Y. Ponsioen, Christopher George Mathew, Paul J. Rutgeerts, Severine A.R.A. Vermeire, Erik Schrumpf, Johannes R. Hov, Michael Peter Manns, Kirsten Muri Boberg, Stefan Schreiber, André Franke, Tom H. Karlsen · 发表于：Hepatology · 年份：2012 · DOI：10.1002/hep.25977 · 被引用次数：201 · 研究领域：Liver Diseases and Immunity、Inflammatory Bowel Disease、Drug Transport and Resistance Mechanisms

UNLABELLED: Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. CONCLUSION: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able...