TY - JOUR
T1 - Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci
AU - Folseraas, Trine
AU - Melum, Espen
AU - Rausch, Philipp
AU - Juran, Brian D.
AU - Ellinghaus, Eva
AU - Shiryaev, Alexey
AU - Laerdahl, Jon K.
AU - Ellinghaus, David
AU - Schramm, Christoph
AU - Weismüller, Tobias J.
AU - Gotthardt, Daniel Nils
AU - Hov, Johannes Roksund
AU - Clausen, Ole Petter
AU - Weersma, Rinse K.
AU - Janse, Marcel
AU - Boberg, Kirsten Muri
AU - Björnsson, Einar
AU - Marschall, Hanns Ulrich
AU - Cleynen, Isabelle
AU - Rosenstiel, Philip
AU - Holm, Kristian
AU - Teufel, Andreas
AU - Rust, Christian
AU - Gieger, Christian
AU - Wichmann, H. Erich
AU - Bergquist, Annika
AU - Ryu, Euijung
AU - Ponsioen, Cyriel Y.
AU - Runz, Heiko
AU - Sterneck, Martina
AU - Vermeire, Severine
AU - Beuers, Ulrich
AU - Wijmenga, Cisca
AU - Schrumpf, Erik
AU - Manns, Michael P.
AU - Lazaridis, Konstantinos N.
AU - Schreiber, Stefan
AU - Baines, John F.
AU - Franke, Andre
AU - Karlsen, Tom H.
N1 - Funding Information:
The study was supported by The Norwegian PSC Research Center ( http://ous-research.no/nopsc/ ) and the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) and the Integrated Research and Treatment Center – Transplantation (reference number: 01EO0802) and the PopGen biobank ( http://www.popgen.de ). The US part of the study was supported by the NIH (DK 84960). The project received infrastructure support through the Norwegian Functional Genomics Programme (FUGE) via the “CIGENE” platform ( http://www.cigene.no/ ), the Research Computing Services at the University of Oslo and the DFG excellence cluster “Inflammation at Interfaces” ( http://www.inflammation-at-interfaces.de/ ).
PY - 2012/8
Y1 - 2012/8
N2 - 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; pcombined = 2.1 × 10-8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (prepl <0.05). FUT2 at chromosome 19q13 (rs602662; pcomb = 1.9 × 10-6, rs281377; pcomb = 2.1 × 10-6 and rs601338; pcomb = 2.7 × 10 -6) is notable due 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.
AB - 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; pcombined = 2.1 × 10-8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (prepl <0.05). FUT2 at chromosome 19q13 (rs602662; pcomb = 1.9 × 10-6, rs281377; pcomb = 2.1 × 10-6 and rs601338; pcomb = 2.7 × 10 -6) is notable due 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.
KW - Genome-wide association study
KW - Immunogenetics
KW - Primary sclerosing cholangitis
KW - Single nucleotide polymorphism
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U2 - 10.1016/j.jhep.2012.03.031
DO - 10.1016/j.jhep.2012.03.031
M3 - Article
C2 - 22521342
AN - SCOPUS:84863981813
SN - 0168-8278
VL - 57
SP - 366
EP - 375
JO - Journal of hepatology
JF - Journal of hepatology
IS - 2
ER -