Gastroenterology
Volume 138, Issue 3 , Pages 1102-1111 , March 2010

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

  • Tom H. Karlsen

      Affiliations

    • Medical Department, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway
    • Corresponding Author InformationReprint requests Address requests for reprints to: Tom H. Karlsen, MD, PhD, Medical Department, Rikshospitalet University Hospital, 0027 Oslo, Norway. fax: (47) 23074869
  • ,
  • Andre Franke

      Affiliations

    • Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Espen Melum

      Affiliations

    • Medical Department, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway
  • ,
  • Arthur Kaser

      Affiliations

    • Department of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria
  • ,
  • Johannes Roksund Hov

      Affiliations

    • Medical Department, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway
  • ,
  • Tobias Balschun

      Affiliations

    • Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Benedicte A. Lie

      Affiliations

    • Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway
  • ,
  • Annika Bergquist

      Affiliations

    • Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Stockholm, Sweden
  • ,
  • Christoph Schramm

      Affiliations

    • 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • ,
  • Tobias J. Weismüller

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  • ,
  • Daniel Gotthardt

      Affiliations

    • Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany
  • ,
  • Christian Rust

      Affiliations

    • Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany
  • ,
  • Eva E.R. Philipp

      Affiliations

    • Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Teresa Fritz

      Affiliations

    • Department of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria
  • ,
  • Liesbet Henckaerts

      Affiliations

    • Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
  • ,
  • Rinse K. Weersma

      Affiliations

    • Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, The Netherlands
  • ,
  • Pieter Stokkers

      Affiliations

    • Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • ,
  • Cyriel Y. Ponsioen

      Affiliations

    • Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • ,
  • Cisca Wijmenga

      Affiliations

    • Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
  • ,
  • Martina Sterneck

      Affiliations

    • 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • ,
  • Michael Nothnagel

      Affiliations

    • Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Jochen Hampe

      Affiliations

    • Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Andreas Teufel

      Affiliations

    • 1st Department of Medicine, University of Mainz, Mainz, Germany
  • ,
  • Heiko Runz

      Affiliations

    • Department of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany
  • ,
  • Philip Rosenstiel

      Affiliations

    • Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  • ,
  • Adolf Stiehl

      Affiliations

    • Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany
  • ,
  • Severine Vermeire

      Affiliations

    • Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
  • ,
  • Ulrich Beuers

      Affiliations

    • Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • ,
  • Michael P. Manns

      Affiliations

    • Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  • ,
  • Erik Schrumpf

      Affiliations

    • Medical Department, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway
  • ,
  • Kirsten Muri Boberg

      Affiliations

    • Medical Department, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway
  • ,
  • Stefan Schreiber

      Affiliations

    • Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
    • Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany

Received 10 August 2009 ,Accepted 18 November 2009.

References 

  1. Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut. 1980;21:870–877
  2. Boberg KM, Aadland E, Jahnsen J, et al. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33:99–103
  3. Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003;125:1364–1369
  4. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56:48–54
  5. Bergquist A, Montgomery SM, Bahmanyar S, et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2008;6:939–943
  6. Schrumpf E, Fausa O, Forre O, et al. HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease. Scand J Gastroenterol. 1982;17:187–191
  7. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol. 2007;13:5421–5431
  8. Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889–899
  9. Franke A, Balschun T, Karlsen TH, et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet. 2008;40:713–715
  10. Fisher SA, Tremelling M, Anderson CA, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008;40:710–712
  11. Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41:216–220
  12. Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319–1323
  13. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575
  14. WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678
  15. Fukushima K, Ueno Y. Bioinformatic approach for understanding the heterogeneity of cholangiocytes. World J Gastroenterol. 2006;12:3481–3486
  16. Wang X, Seed B. A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003;31:e154
  17. Baranzini SE, Wang J, Gibson RA, et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet. 2009;18:767–778
  18. Comabella M, Craig DW, Camina-Tato M, et al. Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms. PLoS ONE. 2008;3:e3490
  19. Weersma RK, Stokkers PC, Cleynen I, et al. Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort. Am J Gastroenterol. 2009;104:630–638
  20. Filmus J, Capurro M, Rast J. Glypicans. Genome Biol. 2008;9:224
  21. Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97
  22. Goyette P, Lefebvre C, Ng A, et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol. 2008;1:131–138
  23. Capurro MI, Xiang YY, Lobe C, et al. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 2005;65:6245–6254
  24. Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002;298:714–719
  25. Keitel V, Donner M, Winandy S, et al. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008;372:78–84
  26. Keitel V, Reinehr R, Gatsios P, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45:695–704
  27. Keitel V, Cupisti K, Ullmer C, et al. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009;50:861–870
  28. Pall H, Zielenski J, Jonas MM, et al. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J Pediatr. 2007;151:255–259
  29. Zhou YQ, Chen YQ, Fisher JH, et al. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. J Biol Chem. 2002;277:38104–38110
  30. Karlsen TH, Boberg KM, Olsson M, et al. Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis. J Hepatol. 2007;46:899–906
  31. Vandiedonck C, Beaurain G, Giraud M, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Natl Acad Sci U S A. 2004;101:15464–15469
  32. Loftus EV, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–96
  33. Karlsen TH, Hampe J, Wiencke K, et al. Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis. Am J Gastroenterol. 2007;102:115–121
  34. Bungay HK, Buchel OC, Cummings F, et al. Prevalence and determinants of primary sclerosing cholangitis in a cohort of patients with inflammatory bowel disease and normal liver function tests. Gut. 2008;57:A107
  35. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–1463

 Conflicts of interest The authors disclose no conflicts.

 Funding The study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network and the PopGen biobank (www.popgen.de). The project received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces” (www.inflammation-at-interfaces.de) and the Norwegian PSC research center (www.rikshospitalet.no/nopsc).

PII: S0016-5085(09)02063-0

doi: 10.1053/j.gastro.2009.11.046

Gastroenterology
Volume 138, Issue 3 , Pages 1102-1111 , March 2010