Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

6533b834fe1ef96bd129d5a8

RESEARCH PRODUCT

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

Eva E. R. Philipp Andreas Teufel Tom H. Karlsen Erik Schrumpf Johannes R. Hov Benedicte A. Lie Cyriel Y. Ponsioen Cisca Wijmenga Espen Melum Adolf Stiehl Heiko Runz Liesbet Henckaerts Daniel Gotthardt Jochen Hampe Andre Franke Christoph Schramm Philip Rosenstiel Tobias Balschun Pieter C. F. Stokkers Ulrich Beuers Stefan Schreiber Michael Nothnagel Teresa Fritz Arthur Kaser Annika Bergquist Rinse K. Weersma Kirsten Muri Boberg Martina Sterneck Tobias J. Weismüller Christian Rust Michael P. Manns Severine Vermeire

subject

LOCI Macrophage Stimulating 1 (Hepatocyte Growth Factor-Like)Genome-wide association study SUSCEPTIBILITY Gene Frequency HLA Antigens Risk Factors HEPATOCELLULAR-CARCINOMA Odds Ratio Bile Biliary Tract INCREASED RISK Oligonucleotide Array Sequence Analysis Gastroenterology MULTIPLE-SCLEROSIS CROHNS-DISEASE Europe Phenotype ULCERATIVE-COLITIS Inflammation Mediators SNP array Cholangitis Sclerosing Single-nucleotide polymorphism Locus (genetics)Human leukocyte antigen Biology Polymorphism Single Nucleotide Risk Assessment Cell Line Primary sclerosing cholangitis Glypicans Genetic predisposition medicine Humans Genetic Predisposition to Disease Gene Silencing ACID RECEPTOR TGR5 Genetic association Inflammation Chi-Square Distribution Hepatology Gene Expression Profiling Glypican 6 medicine.disease GENE G-Protein-Coupled Bile Acid Receptor 1 Case-Control Studies Immunology Colitis Ulcerative Genome-Wide Association Study INFLAMMATORY-BOWEL-DISEASE

description

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 × 10 −26 ; and rs2844559: OR, 4.7; 95% CI, 3.5–6.4; P = 4.2 × 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.

year	journal	country	edition	language
2010-03-01	Gastroenterology

https://doi.org/10.1053/j.gastro.2009.11.046