A Positive Causal Influence of IL-18 Levels on the Risk of T2DM: A Mendelian Randomization Study

• Main Authors: He Zhuang, Junwei Han, Liang Cheng, Shu-Lin Liu
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-04-01
• Series: Frontiers in Genetics
• Subjects: interleukin-18 levels; type 2 diabetes mellitus; casual effect; Mendelian randomization; genome-wide association studies
• Online Access: https://www.frontiersin.org/article/10.3389/fgene.2019.00295/full

A large number of clinical studies have shown that interleukin-18 (IL-18) plasma levels are positively correlated with the pathogenesis and development of type 2 diabetes mellitus (T2DM), but it remains unclear whether IL-18 causes T2DM, primarily due to the influence of reverse causality and residual confounding factors. Genome-wide association studies have led to the discovery of numerous common variants associated with IL-18 and T2DM and opened unprecedented opportunities for investigating possible associations between genetic traits and diseases. In this study, we employed a two-sample Mendelian randomization (MR) method to analyze the causal relationships between IL-18 plasma levels and T2DM using IL18-related SNPs as genetic instrumental variables (IVs). We first selected eight SNPs that were significantly associated with IL-18 but independent of T2DM. We then used these SNPs as IVs to evaluate their effects on T2DM using the inverse-variance weighted (IVW) method. Finally, we conducted sensitivity analysis and MR-Egger regression analysis to evaluate the heterogeneity and pleiotropic effects of each variant. The results based on the IVW method demonstrate that high IL-18 plasma levels significantly increase the risk of T2DM, and no heterogeneity or pleiotropic effects appeared after the sensitivity and MR-Egger analyses.