title: Genome-wide association analysis in primary sclerosing cholangitis.
abstract: OBJECTIVE
  We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.
  
  
  METHODS
  A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls).
  
  
  RESULTS
  The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes.
  
  
  CONCLUSIONS
  Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.
authors: Medical Department, Rikshospitalet University Hospital and University of Oslo, 0027 Oslo, Norway. t.h.karlsen@klinmed.uio.no
authors: Tom H
authors: TH
authors: Karlsen
authors: Andre
authors: A
authors: Franke
authors: Espen
authors: E
authors: Melum
authors: Arthur
authors: A
authors: Kaser
authors: Johannes Roksund
authors: JR
authors: Hov
authors: Tobias
authors: T
authors: Balschun
authors: Benedicte A
authors: BA
authors: Lie
authors: Annika
authors: A
authors: Bergquist
authors: Christoph
authors: C
authors: Schramm
authors: Tobias J
authors: TJ
authors: Weismüller
authors: Daniel
authors: D
authors: Gotthardt
authors: Christian
authors: C
authors: Rust
authors: Eva E R
authors: EE
authors: Philipp
authors: Teresa
authors: T
authors: Fritz
authors: Liesbet
authors: L
authors: Henckaerts
authors: Rinse K
authors: RK
authors: Weersma
authors: Pieter
authors: P
authors: Stokkers
authors: Cyriel Y
authors: CY
authors: Ponsioen
authors: Cisca
authors: C
authors: Wijmenga
authors: Martina
authors: M
authors: Sterneck
authors: Michael
authors: M
authors: Nothnagel
authors: Jochen
authors: J
authors: Hampe
authors: Andreas
authors: A
authors: Teufel
authors: Heiko
authors: H
authors: Runz
authors: Philip
authors: P
authors: Rosenstiel
authors: Adolf
authors: A
authors: Stiehl
authors: Severine
authors: S
authors: Vermeire
authors: Ulrich
authors: U
authors: Beuers
authors: Michael P
authors: MP
authors: Manns
authors: Erik
authors: E
authors: Schrumpf
authors: Kirsten Muri
authors: KM
authors: Boberg
authors: Stefan
authors: S
authors: Schreiber
mesh_terms: D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D016009:Chi-Square Distribution; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000276:immunology; D003093:Colitis, Ulcerative / Q000235:genetics; D005060:Europe; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: C120300:GPC6 protein, human; D053673:Glypicans; D006680:HLA Antigens; D018836:Inflammation Mediators