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A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

Nature Genetics volume 39, pages 827–829 (2007)Cite this article

Abstract

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 × 10−7) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5′ of IL21; meta-analysis P = 1.3 × 10−14, odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

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Figure 1: Analysis of chromosome 4q27 region around rs13119723.

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Acknowledgements

We thank C.A. Mein and the Barts and The London Genome Centre for advice and genotyping support; D. Simpkin, T. Dibling and C. Hand for genotyping (Sanger Institute); M.J. Caulfield for advice on study design; D.P. Kelsell for comments on the manuscript; D. Strachan and W.L. McArdle for 1958 Birth Cohort samples; A. Monsuur for patient recruitment; G. Meijer and J. Meijer for histology review; K. Duran for DNA extraction; H. van Someren for clinical database management (The Netherlands); A. Ryan, G. Turner, M. Abuzakouk, N. Kennedy, F. Stevens and C. O'Morain for patient and control recruitment and sample management (Ireland). We thank J. Loveland for EST annotation and checking. We thank the Wellcome Trust Centre for Human Genetics, University of Oxford, for computing facilities. We thank all affected individuals and controls for participating in this study. We acknowledge funding from Coeliac UK; the Coeliac Disease Consortium (an innovative cluster approved by The Netherlands Genomics Initiative and partly funded by the Dutch government (grant BSIK03009)); The Netherlands Genomics Initiative (grant 050-72-425); The Netherlands Organization for Scientific Research (grant 901-04-219); the Science Foundation Ireland and the Wellcome Trust (GR068094MA Clinician Scientist Fellowship to D.A.v.H.; New Blood Fellowship to R.M. and support for the work of R.McG. and P.D.). The authors acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02.

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Author notes

  1. Lude Franke, Karen A Hunt and Rhian Gwilliam: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Gastroenterology, Institute of Cell and Molecular Science, Queen Mary University of London, London, E1 2AT, UK

    David A van Heel, Karen A Hunt, Parveen Kumar & Raymond J Playford

  2. Department of Biomedical Genetics, Complex Genetics Section, University Medical Center Utrecht, Utrecht, 3584, CG, The Netherlands

    Lude Franke, Alexandra Zhernakova & Cisca Wijmenga

  3. Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK

    Rhian Gwilliam, Mike Inouye, Graeme Bethel, William M McLaren, Ralph McGinnis & Panos Deloukas

  4. Genetics Department, University Medical Center Groningen, Groningen, 9700, RB, The Netherlands

    Martin C Wapenaar & Cisca Wijmenga

  5. Transplant Immunology, Oxford Transplant Centre, Churchill Hospital, Oxford, OX3 7LJ, UK

    Martin C N M Barnardo

  6. Department of Gastroenterology, Derbyshire Royal Infirmary, London Road, Derby, DE1 2QY, UK

    Geoffrey K T Holmes

  7. Departments of Clinical Medicine and Immunology, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

    Con Feighery, Dermot Kelleher & Ross McManus

  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK

    Derek Jewell & Lon R Cardon

  9. Gastroenterology Unit, University of Oxford, Oxford, OX3 7BN, UK

    Simon Travis

  10. Gastroenterology Section, Imperial College London, Hammersmith Hospital, London, W12 0HS, UK

    Julian RF Walters

  11. Department of Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK

    David S Sanders

  12. Department of Gastroenterology, St. James's University Hospital, Leeds, LS9 7TF, UK

    Peter Howdle

  13. Department of Gastroenterology, Llandough Hospital, Penarth, CF64 2XX, UK

    Jill Swift

  14. Department of Paediatric Gastroenterology, Leiden University Medical Center, Leiden, 2300, RC, The Netherlands

    M Luisa Mearin

  15. Department of Pediatric Gastroenterology, Vrije University Medical Center, Amsterdam, 1007, MB, The Netherlands

    M Luisa Mearin

  16. Department of Gastroenterology, Vrije University Medical Center, Amsterdam, 1007, MB, The Netherlands

    Chris J Mulder

Authors
  1. David A van Heel
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  2. Lude Franke
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  3. Karen A Hunt
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  6. Mike Inouye
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  7. Martin C Wapenaar
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  8. Martin C N M Barnardo
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  9. Graeme Bethel
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  10. Geoffrey K T Holmes
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  14. Parveen Kumar
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  15. Simon Travis
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  16. Julian RF Walters
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  17. David S Sanders
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  18. Peter Howdle
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  19. Jill Swift
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  20. Raymond J Playford
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  21. William M McLaren
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  22. M Luisa Mearin
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  23. Chris J Mulder
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  24. Ross McManus
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  25. Ralph McGinnis
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  26. Lon R Cardon
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  28. Cisca Wijmenga
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Corresponding author

Correspondence to David A van Heel.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Summary of genome-wide association scan results. (PDF 1408 kb)

Supplementary Fig. 2

Linkage disequilibrium and haplotype analysis of the 4q27 region. (PDF 795 kb)

Supplementary Fig. 3

Quantitative RT-PCR analysis of expression of genes in the 4q27 region in duodenal tissue. (PDF 63 kb)

Supplementary Table 1

Characteristics of subjects. (PDF 16 kb)

Supplementary Table 2

Classical HLA type and rs2187668 genotype. (PDF 15 kb)

Supplementary Table 3

Genome-wide association and replication results. (PDF 82 kb)

Supplementary Table 4

4q27 SNPs and haplotypes in three collections. (PDF 142 kb)

Supplementary Methods (PDF 105 kb)

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van Heel, D., Franke, L., Hunt, K. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39, 827–829 (2007). https://doi.org/10.1038/ng2058

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