Mendelian randomization study for the roles of IL-18 and IL-1 receptor antagonist in the development of inflammatory bowel disease

Background and aims: IL-1 and IL-18 play important roles in intestine barrier integrity maintenance and in-flammatory response. However, their net effects on the risk of IBD are still inconclusive. Here, we used Men-delian randomization (MR) approaches to investigate the causal associations of IL-18 and IL-1Ra (receptor antagonist) on the risks of IBD and subtypes.Methods: For IL-18, both three-sample and two-sample MR approaches were used for the causal inferences. In three-sample MR, three single nucleotide polymorphisms (SNPs) and the effect values were extracted from two quantitative trait loci (pQTL) datasets with non-overlapping populations. In two-sample MR, we extracted ge-netic instruments information from the same larger pQTL dataset. For IL-1Ra, we applied the two-sample MR method with summary-statistics from the larger pQTL dataset. Summary-level results of three large IBD/CD/UC genome-wide association studies in European ancestry were employed. Inverse-variance weighted method, various sensitivity analyses and meta-analysis were performed to give causal estimates, detect heterogeneity and correct for outliers.Results: We observed consistent positive causal effects of IL-18 on all three major outcomes using three-sample MR, with meta-analyses odds ratios (ORs) equal to 1.240 (IBD), 1.199 (CD) and 1.274 (UC) respectively. The two-sample MR demonstrated similar results. Moreover, genetically predicted IL-1Ra is inversely associated with the risk of IBD/UC/CD with ORs equal to 0.915 (IBD), 0.902 (CD) and 0.899 (UC) respectively in meta-analyses.Conclusions: This study suggested genetically predicted IL-18 and IL-1Ra level are causally associated with an increased and decreased risk of IBD and subtypes.