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

Nature Genetics volume 40, pages 1319–1323 (2008)Cite this article

Abstract

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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Acknowledgements

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).

Author information

Author notes

  1. Andre Franke, Tobias Balschun and Tom H Karlsen: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, 24105, Germany

    Andre Franke, Tobias Balschun, Jurgita Sventoraityte, David Ellinghaus, Philip Rosenstiel & Stefan Schreiber

  2. Medical Department, Rikshospitalet University Hospital, Oslo, 0027, Norway

    Tom H Karlsen & Morten H Vatn

  3. popgen Biobank, Christian-Albrechts-University Kiel, Kiel, 24105, Germany

    Susanna Nikolaus & Christian Sina

  4. Department of General Internal Medicine, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, 24105, Germany

    Susanna Nikolaus, Christian Sina & Stefan Schreiber

  5. Max-Planck Institute for Informatics, Saarbrücken, 66123, Germany

    Gabriele Mayr, Francisco S Domingues & Mario Albrecht

  6. Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, 24105, Germany

    Michael Nothnagel & Michael Krawczak

  7. Department of Medical and Molecular Genetics, King's College London School of Medicine, London, SE1 9RT, UK

    Clive M Onnie & Christopher G Mathew

  8. Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, 9700, RB, The Netherlands

    Rinse K Weersma

  9. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, 1105, AZ, The Netherlands

    Pieter C F Stokkers

  10. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, 9700, RB, The Netherlands

    Cisca Wijmenga

  11. Department of Biology, School of Medicine, University of Athens, Athens, 11527, Greece

    Maria Gazouli

  12. Division of Community Health Sciences, St. Georges's University, London, SW17 0RE, UK

    David Strachan

  13. Department of Social Medicine, ALSPAC, University of Bristol, Bristol, BS8 1TQ, UK

    Wendy L McArdle

  14. Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, 3000, Belgium

    Séverine Vermeire & Paul Rutgeerts

  15. Faculty of Medicine, Epigen, Akershus University Hospital, Oslo, 1474, Norway

    Morten H Vatn

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  1. Andre Franke
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the IBSEN study group

Contributions

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.

Corresponding author

Correspondence to Stefan Schreiber.

Additional information

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). https://doi.org/10.1038/ng.221

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