MPI für Evolutionsbiologie / Guest Group Evolutionary Genomics |
|Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci|
|Authors:||Folseraas, Trine; Melum, Espen; Rausch, Philipp; Juran, Brian D.; Ellinghaus, Eva; Shiryaev, Alexey; Laerdahl, Jon K.; Ellinghaus, David; Schramm, Christoph; Weismüller, Tobias J.; Gotthardt, Daniel Nils; Hov, Johannes Roksund; Clausen, Ole Petter; Weersma, Rinse K.; Janse, Marcel; Boberg, Kirsten Muri; Björnsson, 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, Cisca; Schrumpf, Erik; Manns, Michael P.; Lazaridis, Konstantinos N.; Schreiber, Stefan; Baines, John F.; Franke, Andre; Karlsen, Tom H.|
|Date of Publication (YYYY-MM-DD):||2012|
|Title of Journal:||Journal of Hepatology|
|Volume:||article in press|
|Review Status:||not specified|
|Abstract / Description:||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 (preplication <0.05) in the replication.
The most robust novel association was detected at chromosome
1p36 (rs3748816; pcombined = 2.1 108) 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 = 1.9 106,
rs281377; pcomb = 2.1 106 and rs601338; pcomb = 2.7 106)
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.
|Free Keywords:||primary sclerosing cholangitis; genome-wide association study; single nucleotide polymorphism; immunogenetics.|
|External Publication Status:||published|
|Affiliations:||MPI für Evolutionsbiologie/Guest Group Evolutionary Genomics|
|External Affiliations:||Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Institute for Experimental Medicine, Christian-Albrechts-University, Kiel, Germany; Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, United States; Institute of Clinical Molecular Biology, Christian- lbrechts-University, Kiel, Germany; Centre for Molecular Biology and Neuroscience (CMBN) and Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Bioinformatics Core Facility, Department of Informatics, University of Oslo, Oslo, Norway; 1st Department of Medicine, University Medical Center Hamburg- ppendorf, Hamburg, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center-Transplantation (IFB-tx), Hannover Medical School, Hannover, Germany; Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany; Division of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, The Netherlands; Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy and University Hospital, Gothenburg, Sweden; Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium; 181st Department of Medicine, University of Mainz, Mainz, Germany; Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Center Munich, GermanResearch Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology I, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Klinikum Grosshadern, Munich, Germany; Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Stockholm, Sweden; Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States; Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany; Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; Department for General Internal Medicine, Christian- lbrechts-University, Kiel, Germany; Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway|
|Identifiers:||ISSN:0168-8278 (print) [ID-No:1] |
ISSN:1600-0641 (online) [ID-No:2]
LOCALID:2926/S 39271 [Listen-Nummer/S-Nummer]
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