Article abstract
Nature Genetics 40, 395 - 402 (2008)
Published online: 2 March 2008 | doi:10.1038/ng.102
Newly identified genetic risk variants for celiac disease related to the immune response
Karen A Hunt1, Alexandra Zhernakova2, Graham Turner3, Graham A R Heap1, Lude Franke2, Marcel Bruinenberg4, Jihane Romanos4, Lotte C Dinesen5, Anthony W Ryan3, Davinder Panesar1, Rhian Gwilliam6, Fumihiko Takeuchi6, William M McLaren6, Geoffrey K T Holmes7, Peter D Howdle8, Julian R F Walters9, David S Sanders10, Raymond J Playford1, Gosia Trynka4, Chris J J Mulder11, M Luisa Mearin12,13, Wieke H M Verbeek11, Valerie Trimble3, Fiona M Stevens14, Colm O'Morain3, Nicholas P Kennedy3, Dermot Kelleher3, Daniel J Pennington1, David P Strachan15, Wendy L McArdle16, Charles A Mein17, Martin C Wapenaar4, Panos Deloukas6, Ralph McGinnis6, Ross McManus3,18, Cisca Wijmenga2,4,18 & David A van Heel1,18
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.
- Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
- Complex Genetics Section, Department of Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
- Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
- Genetics Department, University Medical Center and Groningen University, 9700 RB Groningen, The Netherlands.
- Gastroenterology Unit, University of Oxford, Oxford OX3 7BN, UK.
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
- Department of Gastroenterology, Derbyshire Royal Infirmary, London Road, Derby DE1 2QY, UK.
- Academic Medical Unit, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK.
- Gastroenterology Section, Imperial College London, Hammersmith Hospital, London W12 0HS, UK.
- Department of Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
- Department of Gastroenterology, VU Medical Center, 1007 MB Amsterdam, The Netherlands.
- Department of Pediatric Gastroenterology, VU Medical Center, 1007 MB Amsterdam, The Netherlands.
- Department of Paediatric Gastroenterology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
- Department of Medicine, National University of Ireland, Galway, Ireland.
- Division of Community Health Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
- Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.
- The Genome Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
- These authors contributed equally to this work.
Correspondence to: David A van Heel1,18 e-mail: d.vanheel@qmul.ac.uk