Letter abstract
Nature Genetics 40, 1319 - 1323 (2008)
Published online: 5 October 2008 | doi:10.1038/ng.221
Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility
Andre Franke1,17, Tobias Balschun1,17, Tom H Karlsen2,17, Jurgita Sventoraityte1, Susanna Nikolaus3,4, Gabriele Mayr5, Francisco S Domingues5, Mario Albrecht5, Michael Nothnagel6, David Ellinghaus1, Christian Sina3,4, Clive M Onnie7, Rinse K Weersma8, Pieter C F Stokkers9, Cisca Wijmenga10, Maria Gazouli11, David Strachan12, Wendy L McArdle13, Séverine Vermeire14, Paul Rutgeerts14, Philip Rosenstiel1, Michael Krawczak6, Morten H Vatn2,15, the IBSEN study group16, Christopher G Mathew7 & Stefan Schreiber1,4
Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 
10-12; OR = 1.46 (1.31–1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01–1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.
- Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
- Medical Department, Rikshospitalet University Hospital, Oslo 0027, Norway.
- popgen Biobank, Christian-Albrechts-University Kiel, Kiel 24105, Germany.
- Department of General Internal Medicine, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel 24105, Germany.
- Max-Planck Institute for Informatics, Saarbrücken 66123, Germany.
- Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel 24105, Germany.
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London SE1 9RT, UK.
- Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen 9700 RB, The Netherlands.
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
- Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen 9700 RB, The Netherlands.
- Department of Biology, School of Medicine, University of Athens, Athens 11527, Greece.
- St. Georges's University, Division of Community Health Sciences, London SW17 0RE, UK.
- ALSPAC, Department of Social Medicine, University of Bristol, Bristol BS8 1TQ, UK.
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven 3000, Belgium.
- Faculty of Medicine, Epigen, Akershus University Hospital, 1474 Oslo, Norway.
- A full list of members is provided in the Supplementary Note online.
- These authors contributed equally to this work.
Correspondence to: Stefan Schreiber1,4 e-mail: s.schreiber@mucosa.de
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