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Folseraas, T.* ; Melum, E.* ; Rausch, P.* ; Juran, B.D.* ; Ellinghaus, E.* ; Shiryaev, A.* ; Laerdahl, J.K.* ; Ellinghaus, D.* ; Schramm, C.* ; Weismüller, T.J.* ; Gotthard, D.N.* ; Hov, J.R.* ; Clausen, O.P.* ; Weersma, R.K.* ; Janse, M.* ; Boberg, K.M.* ; Björnsson, E.* ; Marschall, H.U.* ; Cleynen, I.* ; Rosenstiel, P.* ; Holm, K.* ; Teufel, A.* ; Rust, C.* ; Gieger, C. ; Wichmann, H.-E. ; Bergquist, A.* ; Ryu, E.J.* ; Ponsioen, C.Y.* ; Runz, H.* ; Sterneck, M.* ; Vermeire, S.* ; Beuers, U.* ; Wijmenga, C.* ; Schrumpf, E.* ; Manns, M.P.* ; Lazaridis, K.N.* ; Schreiber, S.* ; Baines, J.F.* ; Franke, A.* ; Karlsen, T.H.*

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

J. Hepatol. 57, 366-375 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Primary Sclerosing Cholangitis ; Genome-wide Association Study ; Single Nucleotide Polymorphism ; Immunogenetics; T-Lymphocyte Attenuator; Non-Secretor Status; Susceptibility Loci; B-Lymphocyte; Blood-Group; Fut2; Population; Diseases; Gene; Metaanalysis
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Journal Journal of Hepatology
Quellenangaben Volume: 57, Issue: 2, Pages: 366-375 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)