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Newly identified genetic risk variants for celiac disease related to the immune response

Abstract

Our genome-wide association study of celiac disease previously identified risk variants in the IL2IL21 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, IL2IL21, 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.

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Figure 1: Quantile-quantile plot for association results in follow-up samples.
Figure 2: LD structure and association results for eight non-HLA celiac disease–associated regions.
Figure 3: Correlation of rs917997 genotype with whole-blood cis IL18RAP mRNA expression.

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Acknowledgements

We acknowledge funding from Coeliac UK (to D.A.v.H.); the Coeliac Disease Consortium (an innovative cluster approved by The Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to C.W.); the European Union (STREP 036383); The Netherlands Organization for Scientific Research (VICI grant 918.66.620 to C.W.); the Science Foundation Ireland; the Irish Health Research Board; Hitachi Europe Ltd.; and the Wellcome Trust (GR068094MA Clinician Scientist Fellowship to D.A.v.H.; New Blood Fellowship to R. McManus; support for the work of R. McGinnis and P.D.). We thank the Barts and The London Genome Centre for genotyping support; J. Swift, P. Kumar, D.P. Jewell, S.P.L. Travis and K. Moriarty for collection of UKGWAS and additional samples. We 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. We thank A. Monsuur for DUTCH subject recruitment, G. Meijer and J. Meijer for histology review, K. Duran for DNA extraction, H. van Someren and F. Mulder for clinical database management, M. Plateel and the genotyping facilities at UMCG and UMC Utrecht for technical assistance. We thank M. Abuzakouk, R. McLoughlin, K. Brophy, C. Feighery and J. McPartlin for sample collection. Control DNA for the IRISH collection was supplied by the Irish Blood Transfusion Service and the Trinity College Dublin Biobank. We thank the Wellcome Trust Centre for Human Genetics, University of Oxford for provision of computing facilities and G. McVean for recombination rate data. We thank all individuals with celiac disease and control individuals for participating in this study.

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Authors and Affiliations

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Contributions

L.F. and D.A.v.H. analyzed UK GWAS data, selected SNPs and designed assays for golden gate genotyping. Substantial contributions to sample collections were made by D.A.v.H., L.C.D., G.K.T.H., P.D.H., J.R.F.W. and D.S.S. (UK2 cases); D.P.S. and W.L.M. (1958 cohort controls); C.J.J.M., W.H.M.V. and M.L.M. (Dutch samples); V.T., F.M.S., C.O., N.P.K. and D.K. (Irish samples). UKGWAS genotyping was performed as described in P.D. laboratory2. K.A.H. extracted UKGWAS and UK2 celiac DNA samples and performed UK2 sample Golden Gate genotyping. G. Turner and A.W.R. prepared Irish DNA samples. G. Turner, A.W.R. and K.A.H. performed Irish sample Golden Gate genotyping. UK2 and IRISH genotyping was performed in the C.A.M. laboratory, D.P. performed quality control steps. A.Z. prepared DUTCH celiac and control DNA samples, and A.Z. and J.R. performed DUTCH sample Golden Gate genotyping in the C.W. laboratory. D.A.v.H. and K.A.H. performed final Golden Gate genotype clustering on all samples, with assistance from R.G. L.C.D. and D.A.v.H. collected Paxgene RNA celiac blood samples, G.A.R.H. extracted Paxgene RNA, G.A.R.H. and M.B. performed expression chips in the C.W. laboratory, G.A.R.H. and L.F. analyzed expression data. G. Trynka performed IL18RAP resequencing. M.C.W. processed intestinal biopsies, M.B. and M.C.W. performed expression chips in the C.W. laboratory, M.C.W. and G.A.R.H. analyzed expression data. D.J.P. performed analysis of genes in intestinal T-cell subsets. K.A.H. and G.A.R.H. performed bioinformatics and annotation of celiac risk variant regions. D.A.v.H., R. McManus and C.W. were principal investigators and directed the UK, Irish and Dutch sample collections, respectively; with R.J.P., they designed overall strategy and obtained funding for the study. D.A.v.H. directed the entire study, performed statistical analysis and generated the figures. D.A.v.H. and C.W. wrote the paper. R. McGinnis, F.T. and W.M.M. performed additional statistical analysis.

Corresponding author

Correspondence to David A van Heel.

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Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Table 1, Supplementary Figures 1–3 (PDF 2138 kb)

Supplementary Data 1 (Excel file)

Detailed association results for all markers (XLS 1087 kb)

Supplementary Data 2 (Excel file)

Cis effects of celiac disease associated SNPs on gene expression. (XLS 19 kb)

Supplementary Data 3 (Excel file)

Celiac disease associated SNPs in WTCCC dataset (XLS 33 kb)

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Hunt, K., Zhernakova, A., Turner, G. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40, 395–402 (2008). https://doi.org/10.1038/ng.102

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