Correlation between circulating levels of cytokines and the risk of systemic lupus erythematosus: results from a Mendelian randomization study and bioinformatics analysis

Abstract Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, the etiology of which involves the alterations in circulating cytokine levels. However, the cause-and-effect relationships and in-depth clinical relevance of them remains to be systematically investigated. Methods We conducted a two-sample Mendelian randomization (MR) study using Wald ratio and Delta, inverse-variance weighted (IVW), MR-Egger regression, and the MR pleiotropy residual sum and outlier (MR-PRESSO) methods, to assess the causality of circulating cytokine levels and SLE. Furthermore, we performed an observational study using two datasets, including GSE99967 and GSE121239, to further reveal the association between 27 circulating cytokines and the severity measured by SLEDAI score, as well as lupus nephritis (LN), of SLE. Results In MR analysis, genetically determined elevated CTACK, and IL-18 were associated with an increased risk of SLE, whereas higher level of GRO-a was associated with a 5% decreased risk of SLE. In bioinformatics analysis, we identified 10 cytokines with significant differences between SLE patients and controls. Among them, there were 6 cytokines (MCP1, MIP-1b, CTACK, IP10, HGF, IL-18, IL-13) were identified as associated with clinical severity. Besides, 5 cytokines, including SDF-1a, IL-18, IL-8, IL-4, and TNF, were related with LN and may have good diagnostic value for LN. Moreover, we also predicted 4 compounds might have good binding activities with IL-18, which may have the potential therapeutic effects on SLE. Conclusion The evidence supported a potential causal role of circulating cytokines on the risk of SLE. Targeting IL-18 might be a meaningful strategy for the prevention or treatment of SLE, especially in LN patients.