Genome-wide association analysis in primary sclerosing cholangitis
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Genome-wide association analysis in primary sclerosing cholangitis. / Karlsen, Tom H; Franke, Andre; Melum, Espen; Kaser, Arthur; Hov, Johannes Roksund; Balschun, Tobias; Lie, Benedicte A; Bergquist, Annika; Schramm, Christoph; Weismüller, Tobias J; Gotthardt, Daniel; Rust, Christian; Philipp, Eva E R; Fritz, Teresa; Henckaerts, Liesbet; Weersma, Rinse; Stokkers, Pieter; Ponsioen, Cyriel Y; Wijmenga, Cisca; Sterneck, Martina; Nothnagel, Michael; Hampe, Jochen; Teufel, Andreas; Runz, Heiko; Rosenstiel, Philip; Stiehl, Adolf; Vermeire, Severine; Beuers, Ulrich; Manns, Michael; Schrumpf, Erik; Boberg, Kirsten Muri; Schreiber, Stefan.
In: GASTROENTEROLOGY, Vol. 138, No. 3, 03.2010, p. 1102-1111.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genome-wide association analysis in primary sclerosing cholangitis
AU - Karlsen, Tom H
AU - Franke, Andre
AU - Melum, Espen
AU - Kaser, Arthur
AU - Hov, Johannes Roksund
AU - Balschun, Tobias
AU - Lie, Benedicte A
AU - Bergquist, Annika
AU - Schramm, Christoph
AU - Weismüller, Tobias J
AU - Gotthardt, Daniel
AU - Rust, Christian
AU - Philipp, Eva E R
AU - Fritz, Teresa
AU - Henckaerts, Liesbet
AU - Weersma, Rinse
AU - Stokkers, Pieter
AU - Ponsioen, Cyriel Y
AU - Wijmenga, Cisca
AU - Sterneck, Martina
AU - Nothnagel, Michael
AU - Hampe, Jochen
AU - Teufel, Andreas
AU - Runz, Heiko
AU - Rosenstiel, Philip
AU - Stiehl, Adolf
AU - Vermeire, Severine
AU - Beuers, Ulrich
AU - Manns, Michael
AU - Schrumpf, Erik
AU - Boberg, Kirsten Muri
AU - Schreiber, Stefan
N1 - Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2010/3
Y1 - 2010/3
N2 - BACKGROUND ; AIMS: 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.
AB - BACKGROUND ; AIMS: 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.
KW - Bile
KW - Biliary Tract
KW - Case-Control Studies
KW - Cell Line
KW - Chi-Square Distribution
KW - Cholangitis, Sclerosing
KW - Colitis, Ulcerative
KW - Europe
KW - Gene Expression Profiling
KW - Gene Frequency
KW - Gene Silencing
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Glypicans
KW - HLA Antigens
KW - Humans
KW - Inflammation Mediators
KW - Odds Ratio
KW - Oligonucleotide Array Sequence Analysis
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Risk Assessment
KW - Risk Factors
KW - Journal Article
KW - Meta-Analysis
KW - Multicenter Study
KW - Research Support, Non-U.S. Gov't
U2 - 10.1053/j.gastro.2009.11.046
DO - 10.1053/j.gastro.2009.11.046
M3 - SCORING: Journal article
C2 - 19944697
VL - 138
SP - 1102
EP - 1111
JO - GASTROENTEROLOGY
JF - GASTROENTEROLOGY
SN - 0016-5085
IS - 3
ER -
