Abstract

Our genome-wide association study of celiac disease previously identified risk variants in the IL2–IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 10^-7). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2–IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

1. Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
2. Complex Genetics Section, Department of Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
3. Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
4. Genetics Department, University Medical Center and Groningen University, 9700 RB Groningen, The Netherlands.
5. Gastroenterology Unit, University of Oxford, Oxford OX3 7BN, UK.
6. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
7. Department of Gastroenterology, Derbyshire Royal Infirmary, London Road, Derby DE1 2QY, UK.
8. Academic Medical Unit, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK.
9. Gastroenterology Section, Imperial College London, Hammersmith Hospital, London W12 0HS, UK.
10. Department of Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
11. Department of Gastroenterology, VU Medical Center, 1007 MB Amsterdam, The Netherlands.
12. Department of Pediatric Gastroenterology, VU Medical Center, 1007 MB Amsterdam, The Netherlands.
13. Department of Paediatric Gastroenterology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
14. Department of Medicine, National University of Ireland, Galway, Ireland.
15. Division of Community Health Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
16. Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.
17. The Genome Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
18. These authors contributed equally to this work.

Correspondence to: David A van Heel^1,18 e-mail: d.vanheel@qmul.ac.uk

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