The Assessment of Interleukin-18 on the Risk of Coronary Heart Disease

Abstract

Background: Observational studies support the inflammation hypothesis in coronary heart disease (CHD). As a pleiotropic proinflammatory cytokine, Interleukin-18 (IL-18), has also been found to be associated with the risk of CHD. However, to our knowledge, the method of Mendelian Randomization has not been used to explore the causal effect of IL-18 on CHD. Objective: To assess the causal effect of IL-18 on the risk of CHD. Methods and Results: Genetic variant instruments for IL-18 were obtained from information of the CHS and InCHIANTI cohort, and consisted of the per-allele difference in mean IL-18 for 16 independent variants that reached genome-wide significance. The per-allele difference in log-odds of CHD for each of these variants was estimated from CARDIoGRAMplusC4D, a two-stage meta -analysis. Two-sample Mendelian Randomization (MR) was then performed. Various MR analyses were used, including weighted inverse-variance, MR-Egger regression, robust regression, and penalized regression. The OR of elevated IL-18 associated with CHD was only 0.005 (95%CI -0.105~0.095; P-value=0.927). Similar results were obtained with the use of MR-Egger regression, suggesting that directional pleiotropy was unlikely biasing these results (intercept -0.050, P-value=0.220). Moreover, results from the robust regression and penalized regression analyses also revealed essentially similar findings. Conclusions: Our findings indicate that, by itself, IL-18 is unlikely to represent even a modest causal factor for CHD risk.