Genome‐wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Issue 3 (17th January 2013)

• Record Type: Journal Article
• Authors: Ellinghaus, David; Folseraas, Trine; Holm, Kristian; Ellinghaus, Eva; Melum, Espen; Balschun, Tobias; Laerdahl, Jon K.; Shiryaev, Alexey; Gotthardt, Daniel N.; 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, Séverine; Schrumpf, Erik; Hov, Johannes R.; Manns, Michael P.; Boberg, Kirsten M.; Schreiber, Stefan; Franke, Andre; Karlsen, Tom H.;
• Is Part Of: Hepatology. Volume 58:Issue 3(2013:Sep.)
• Page Start: 1074
• Page End: 1083
• Publication Date: 2013-01-17
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.25977
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<italic>GPR35</italic>); <italic>P</italic> = 3.0 × 10<sup>−9</sup> 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 (<italic>TCF4</italic>); <italic>P</italic> = 2.61 × 10<sup>−8</sup>, OR (95% CI) = 0.75 (0.68‐0.83)]. In addition, several suggestive PSC associations were detected. The <italic>GPR35</italic> 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 <italic>GPR35</italic> and could possibly alter efficiency of signaling through the <italic>GPR35</italic> receptor. <italic>Conclusion</italic>: 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. <italic>GPR35</italic> shows associations in both UC and PSC, whereas <italic>TCF4</italic> represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (H<sc>EPATOLOGY</sc> 2013;58:1074–1083)</p> </abstract>