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. 2008 Apr;40(4):395-402.
doi: 10.1038/ng.102. Epub 2008 Mar 2.

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

Karen A Hunt  1 , 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

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.

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Figures

Figure 1
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
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
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.
See this image and copyright information in PMC

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