Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

Folseraas, Trine, Melum, Espen, Rausch, Philipp, Juran, Brian D., Ellinghaus, Eva, Shiryaev, Alexey, Laerdahl, Jon K., Ellinghaus, David, Schramm, Christoph, Weismueller, Tobias J., Gotthard, Daniel Nils, Hov, Johannes Roksund, Clausen, Ole Petter, Weersma, Rinse K., Janse, Marcel, Boberg, Kirsten Muri, Bjornsson, Einar, Marschall, Hanns-Ulrich, Cleynen, Isabelle, Rosenstiel, Philip, Holm, Kristian, Teufel, Andreas, Rust, Christian, Gieger, Christian, Wichmann, H. Erich, Bergquist, Annika, Ryu, Euijung, Ponsioen, Cyriel Y., Runz, Heiko, Sterneck, Martina, Vermeire, Severine, Beuers, Ulrich, Wijmenga, Oisca, Schrumpf, Erik, Manns, Michael P., Lazaridis, Konstantinos N., Schreiber, Stefan, Baines, John F., Franke, Andre and Karlsen, Tom H. (2012) Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. Journal of Hepatology, 57 (2). pp. 366-375.

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Abstract

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Document Type: Article
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University > Kiel Marine Science
Refereed: Yes
ISSN: 0168-8278
Projects: Future Ocean
Date Deposited: 14 May 2014 10:12
Last Modified: 14 May 2014 10:12
URI: http://oceanrep.geomar.de/id/eprint/23923

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