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Title: Genome-wide association analysis in sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4
Authors: Ellinghaus, David ×
Folseraas, Trine
Holm, Kristian
Ellinghaus, Eva
Melum, Espen
Balschun, Tobias
Laerdahl, Jon K
Shiryaev, Alexey
Gotthardt, Daniel Nils
Weismüller, Tobias J
Schramm, Christoph
Wittig, Michael
Bergquist, Annika
Björnsson, Einar
Marschall, Hanns-Ulrich
Vatn, Morten
Teufel, Andreas
Rust, Christian
Gieger, Christian
Wichmann, H-Erich
Runz, Heiko
Sterneck, Martina
Rupp, Christian
Braun, Felix
Weersma, Rinse K
Wijmenga, Cisca
Ponsioen, Cyriel Y
Mathew, Christopher G
Rutgeerts, Paul
Vermeire, Severine
Schrumpf, Erik
Hov, Johannes Roksund
Manns, Michael P
Boberg, Kirsten Muri
Schreiber, Stefan
Franke, Andre
Karlsen, Tom H #
Issue Date: Sep-2013
Publisher: W.B. Saunders
Series Title: Hepatology vol:58 issue:3 pages:1074-83
Article number: 10.1002/hep.25977
Abstract: 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 purpose 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 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 GPR35; P=3.0×10(-9) in the overall study population, combined odds ratio (OR; 95% confidence interval (CI)) of 1.39 (1.24-1.55)], and at 18q21 [rs1452787 at 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 to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, while TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2012.).
ISSN: 0270-9139
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Research in GastroIntestinal Disorders
× corresponding author
# (joint) last author

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