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

Celiac disease is common in Western populations with a prevalence of approximately 1%1. HLA-DQ2 or -DQ8 restricted T cell responses to dietary proteins in wheat, rye, and barley lead to small intestinal inflammation and intestinal villous atrophy with consequent clinical features. Several recent immunological advances have identified dominant epitopes, the role of tissue transglutaminase, and the crystal structures of HLA-DQ molecules binding wheat peptides1. However the primary factors (both environmental and genetic) predisposing to disease in the ∼30% of the population carrying susceptible HLA-DQ types are mostly unknown. 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.