Newly identified genetic risk variants for celiac disease related to the immune response - PubMed (original) (raw)
. 2008 Apr;40(4):395-402.
doi: 10.1038/ng.102. Epub 2008 Mar 2.
Alexandra Zhernakova, Graham Turner, Graham A R Heap, Lude Franke, Marcel Bruinenberg, Jihane Romanos, Lotte C Dinesen, Anthony W Ryan, Davinder Panesar, Rhian Gwilliam, Fumihiko Takeuchi, William M McLaren, Geoffrey K T Holmes, Peter D Howdle, Julian R F Walters, David S Sanders, Raymond J Playford, Gosia Trynka, Chris J J Mulder, M Luisa Mearin, Wieke H M Verbeek, Valerie Trimble, Fiona M Stevens, Colm O'Morain, Nicholas P Kennedy, Dermot Kelleher, Daniel J Pennington, David P Strachan, Wendy L McArdle, Charles A Mein, Martin C Wapenaar, Panos Deloukas, Ralph McGinnis, Ross McManus, Cisca Wijmenga, David A van Heel
Affiliations
- PMID: 18311140
- PMCID: PMC2673512
- DOI: 10.1038/ng.102
Newly identified genetic risk variants for celiac disease related to the immune response
Karen A Hunt et al. Nat Genet. 2008 Apr.
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 x 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.
Figures
Figure 1. Quantile-quantile plot for association results in follow-up samples
(a) Q-Q plot of association results (Cochran-Mantel-Haenszel test) for 1020 non-HLA SNPs in UK2, IRISH and DUTCH follow-up samples. Data points in red indicate SNPs shown in Table 1 with P overall < 5×10-7 in all samples including UKGWAS. Straight line indicates expected results under null hypothesis. (b) Q-Q plot of residual association results (Cochran-Mantel-Haenszel test) for 992 non-HLA SNPs, excluding 28 SNPs mapping to the eight celiac associated regions described in Table 1, in UK2, IRISH and DUTCH follow-up samples.
Figure 2. Linkage disequilibrium structure and association results for eight non-HLA celiac disease associated regions
Chromosomal positions based on NCBI build 36 coordinates, showing Ensembl (release 48) genes. Allele count P values are shown for SNPs analysed in UKGWAS samples (black diamonds), and Cochran-Mantel-Haenszel association test P values (red circles) for SNPs analysed in all UKGWAS, UK2, IRISH and DUTCH samples.
Figure 3. Correlation of rs917997 genotype with whole blood cis IL18RAP mRNA expression
Expression levels (bars show group means) were determined in samples from gluten-free diet treated celiac individuals.
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