Genome-wide association analysis in primary sclerosing cholangitis.

Authors:
Tom H Karlsen, Andre Franke, Espen Melum, Arthur Kaser, Johannes Roksund Hov, Tobias Balschun, Benedicte A Lie, Annika Bergquist, Christoph Schramm, Tobias J Weismüller, Daniel Gotthardt, Christian Rust, Eva E R Philipp, Teresa Fritz, Liesbet Henckaerts, Rinse K Weersma, Pieter Stokkers, Cyriel Y Ponsioen, Cisca Wijmenga, Martina Sterneck, Michael Nothnagel, Jochen Hampe, Andreas Teufel, Heiko Runz, Philip Rosenstiel, Adolf Stiehl, Severine Vermeire, Ulrich Beuers, Michael P Manns, Erik Schrumpf, Kirsten Muri Boberg, Stefan Schreiber
Year of publication:
2010
Volume:
138
Issue:
3
Issn:
0016-5085
Journal title abbreviated:
GASTROENTEROLOGY
Journal title long:
Gastroenterology (New York, N.Y. 1943)
Impact factor:
33.883
Abstract:
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.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).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.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.