Replication and Meta-Analysis of 13,000 Cases Defines the Risk for Interleukin-23 Receptor and Autophagy-Related 16-Like 1 Variants in Crohn’s Disease
BACKGROUND/OBJECTIVE: Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn’s disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed.METHODS: British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants inIL23RandATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations betweenIL23RandATG16L1variants and CD, respectively.RESULTS: In the present cohort, both susceptibility variants showed highly significant associations, includingIL23R(rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) andATG16L1(rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and theIL23RorATG16L1polymorphisms (P=0.44 and P=0.24, respectively).CONCLUSION: The present cohort and meta-analysis provides strong evidence that, in addition toCARD15, polymorphisms in bothIL23RandATG16L1alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, onlyATG16L1is relevant to inflammatory bowel disease in the Asian population.