Il23r Haplotypes Provide A Large Population Attributable Risk For Crohn'S Disease

Background: The IL-23 pathway plays a pivotal role in the development of chronic mucosal inflammation seen in the inflammatory bowel diseases. Multiple studies have now established the contribution of the interleukin 23 receptor gene (IL23R) to Crohn's disease (CD) risk in general and of the IL23R R381Q variant in particular. The aim of this work was to estimate the total contribution of this gene to CD risk test using a haplotype approach.Methods: In all, 763 CD Subjects and 254 controls were genotyped tor single nucleotide polymorphisms in the IL23R gene using Illumina and ABI methods. Haplotypes were assigned using PHASEv2 and tested for association With CD by chi-square and permutation.Results: Haplotypes with both increased and decreased risk for CD were observed in 2 of the 4 observed blocks (Block 2 HI: 55.4% control, 64% M P = 0.019 H2: 64.5% control, 54.4% CD. P = 0.006; Block 3 HI: 55.8% control, 64.4% CD, P = 0.013; H2: 47.0% control, 36.6% CD, P = 0.001). The population attributable risk for these haplotypes was substantially larger than that estimated for the IL23R R381Q variant (Block 2 HI and block 3 HI approximate to 20%, compared with approximate to 4% For Block 3 H6, containing the variant).Conclusions: These observations Suggest that IL23R makes a substantial contribution to CD susceptibility, larger than that estimated front the population freqency of the R381Q variant. These observations also support the expectation that funding "hits" from genomewide association studies will be but an important chapter ill the story of unraveling the genctic contribution to CD, rather than the final chapter that brings clarity to all the plot twists of a complicated story.