We tested 310,605 single-nucleotide polymorphisms for association in 778 celiac disease cases and 1422 controls. Outside the HLA, the most significant finding (rs13119723, P=2.0 × 10 −7 , empirical genome-wide significance P=0.045) was in the KIAA1109/Tenr/IL2/IL21 linkage disequilibrium block. Association was independently confirmed in two further collections (strongest at rs6822844, 24kB 5' of IL21, meta-analysis P=1.3 × 10 −14 , OR 0.63), suggesting genetic variation in this region predisposes to celiac disease.Celiac disease is a common (1% prevalence) small intestinal inflammatory condition induced by dietary wheat, rye, and barley. However despite high heritability (estimated at 87% from twin studies1), no non-HLA genetic factors have been identified and convincingly replicated. The majority of celiacs possess HLA-DQ2 (the remainder mostly HLA-DQ82), and how HLA-DQ2 presents cereal peptides to intestinal T cells is understood3. However HLA-DQ2 is common in healthy individuals, demonstrating it is necessary but not sufficient for disease development.

Statement LF and DAvH analysed UK GWAS data, selected SNPs and designed assays for golden gate genotyping. Substantial contributions to sample collections were made by DAvH, LD, GKTH, PH, JRFW, DSS (UK2 cases); DPS, WLMcA (1958 cohort controls); CJM, WV, MLM (DUTCH samples); VT, FMS, COM, NPK, DK (IRISH samples). UKGWAS genotyping was performed as described in PD lab2. KAH extracted UKGWAS and UK2 celiac DNA samples and performed UK2 sample golden gate genotyping. GrahamT and AWR prepared Irish DNA samples. GrahamT, AWR and KAH performed Irish sample golden gate genotyping. UK2 and IRISH genotyping was performed in CAM lab, DP performed quality control steps. AZ prepared DUTCH celiac and control DNA samples, and AZ and JR performed DUTCH sample golden gate genotyping in CW lab. DVH and KAH performed final golden gate genotype clustering on all samples, with assistance from RG. LD and DAvH collected Paxgene RNA celiac blood samples, GH extracted Paxgene RNA, GH and MB performed expression chips in CW lab, GH and LF analysed expression data. GosiaT performed IL18RAP re-sequencing. MCW processed intestinal biopsies, MB and MCW performed expression chips in CW lab, MCW and GH analysed expression data. DJP performed analysis of genes in intestinal T cell subsets. KAH and GH performed bioinformatics and annotation of celiac risk variant regions DAvH, RMM, CW were Principal Investigators and directed respectively the UK, IRISH and DUTCH sample collections and with RJP designed overall strategy and obtained funding for the study. DAvH directed the entire study, performed statistical analysis and generated the figures. DAvH and CW wrote the paper. RMcG, FT and WMMcL performed additional statistical analysis. To identify additional celiac disease susceptibility genes, we recently tested 310,605 SNPs in a genome wide association study of 778 celiac cases and 1,422 population controls from the United Kingdom (UKGWAS), using the Illumina HumanHap300 BeadChip2. The only SNP outside the HLA region demonstrating genome-wide significance was rs13119723 on 4q27, located in a ∼500 kb block of linkage disequilibrium (LD) containing the IL2 and IL21 genes2. Independent replication of SNPs from the IL2-IL21 region was established in both Dutch and Irish collections of celiac patients and controls. We estimate, using the current markers, that the IL2-IL21 region explains less than 1% of the increased familial risk to celiac disease, suggesting that there are additional unidentified susceptibility genes. Since we observed a greater number of significantly associated SNPs in the UKGWAS than would be expected by chance, we proceeded to study >1,000 of the most significant UKGWAS association results in a further 1,643 celiac cases and 3,406 controls from three independent European celiac disease collections. This two-stage strategy, involving a joint analysis of all data, substantially reduces the genotyping requirements versus performing whole genome genotyping on all samples and has been shown to maintain sufficient statistical power3. ...

These data indicate decreased antioxidant status in the face of enhanced free radical activity, and suggest potential therapeutic strategies involving antioxidant repletion.