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Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility


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.

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Figure 1: Regional plot of the confirmed UC association at IL10.


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We wish to thank all individuals with IBD, families and physicians for their cooperation. We gratefully acknowledge the cooperation of the German Crohn and Colitis Foundation (Deutsche Morbus Crohn und Colitis Vereinigung e.V.), the BMBF competence network “IBD” and of the contributing gastroenterologists. Finally, we wish to thank T. Wesse, T. Henke, A. Dietsch, R. Vogler, C.v.d. Lancken and M. Friskovec for expert technical help. We thank T. Wienker and M. Steffens (IMBIE, University of Bonn) for performing the quality control of the GWAS datasets. We thank B.A. Lie and the Norwegian Bone Marrow Donor Registry at Rikshospitalet University Hospital, Oslo, for contributing the healthy Norwegian control population. This study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN), the popgen biobank and the SFB617 “Molecular Mechanisms of Epithelial Defense.” The project received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces.” We acknowledge use of DNA from the 1958 British Birth Cohort collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the UK MRC (grant G0000934) and The Wellcome Trust (grant 068545/Z/02). C.G.M. and C.M.O. were supported by The Wellcome Trust and CORE (UK).

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Authors and Affiliations




A.F., T.B. and J.S. performed the SNP selection, genotyping, data analysis, resequencing, and prepared the figures and tables; T.H.K. helped with data analysis. S.N., C.S. and P. Rosenstiel coordinated the recruitment and collected the phenotype data. M.N. and D.E. helped with data analysis and quality control; G.M., F.S.D. and M.A. performed in silico protein analysis and contributed to writing the manuscript. Norwegian, Belgian, Dutch and Greek patient samples were provided by M.H.V., S.V., P. Rutgeerts, R.K.W., P.C.F.S. and M.G., respectively. W.L.M. and D.S. provided the UK and C.W. the Dutch control samples; M.K. supervised and performed the statistical analysis and edited the paper. C.M.O. and C.G.M. provided the UK patient sample and edited the manuscript. A.F., T.H.K. and S.S. designed and supervised the experiment and wrote the manuscript. All authors approved the final manuscript.

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Correspondence to Stefan Schreiber.

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A full list of members is provided in the Supplementary Note.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–7, Supplementary Figures 1–8 (PDF 7762 kb)

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Franke, A., Balschun, T., Karlsen, T. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40, 1319–1323 (2008).

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