Evaluation of Causal Associations Between Interleukin-18 Levels and Immune-mediated Inflammatory Diseases: a Mendelian Randomization Study

Background: Altered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs.

Methods: We performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations.

Results: We found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (P = 0.009; OR, 1.214; 95% CI, 1.049 - 1.404) and IBD (P < 0.001; OR, 1.142; 95% CI, 1.062 - 1.228), but found no significant associations of IL-18 with RA (P = 0.496; OR, 1.044; 95% CI, 0.923 - 1.180), AS (P = 0.021; OR, 1.181; 95% CI, 1.025 - 1.361), or psoriasis (P = 0.232; OR, 1.198; 95% CI, 0.891 - 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran's Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers.

Conclusions: We have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.