Tags

Type your tag names separated by a space and hit enter

Genome-wide association analysis in primary sclerosing cholangitis.
Gastroenterology 2010; 138(3):1102-11G

Abstract

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.

Pub Type(s)

Journal Article
Meta-Analysis
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19944697

Citation

Karlsen, Tom H., et al. "Genome-wide Association Analysis in Primary Sclerosing Cholangitis." Gastroenterology, vol. 138, no. 3, 2010, pp. 1102-11.
Karlsen TH, Franke A, Melum E, et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010;138(3):1102-11.
Karlsen, T. H., Franke, A., Melum, E., Kaser, A., Hov, J. R., Balschun, T., ... Schreiber, S. (2010). Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology, 138(3), pp. 1102-11. doi:10.1053/j.gastro.2009.11.046.
Karlsen TH, et al. Genome-wide Association Analysis in Primary Sclerosing Cholangitis. Gastroenterology. 2010;138(3):1102-11. PubMed PMID: 19944697.
* Article titles in AMA citation format should be in sentence-case
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 K, 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 P, AU - Schrumpf,Erik, AU - Boberg,Kirsten Muri, AU - Schreiber,Stefan, Y1 - 2009/11/26/ PY - 2009/08/10/received PY - 2009/11/05/revised PY - 2009/11/18/accepted PY - 2009/12/1/entrez PY - 2009/12/1/pubmed PY - 2010/3/26/medline SP - 1102 EP - 11 JF - Gastroenterology JO - Gastroenterology VL - 138 IS - 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/19944697/Genome_wide_association_analysis_in_primary_sclerosing_cholangitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(09)02063-0 DB - PRIME DP - Unbound Medicine ER -