A two-sample Mendelian randomization study to explore the causal relationship between immune inflammatory factors and systemic lupus erythematosus

Background The effect of inflammatory factors on systemic lupus erythematosus has now been widely recognized, however, causal relationship between inflammatory factors and SLE pathogenesis is uncertain. Methods Aggregate statistics for each inflammatory factor and immune feature are publicly available from the Genome-Wide Association Study catalog. This dataset includes a total of 91 inflammatory factors and 731 immune phenotypes, The initial GWAS of immune features used data from 3,757 individuals of European descent. Correlations were examined after adjusting for covariates. The overall impact of inflammatory on SLE can be dissected into the direct and indirect effects. The inverse variance weighing method is a standard MR method for causal analysis. Sensitivity analysis was also perform to optimize the reliability and accuracy of the results. Results Potential association was identified between the levels of caspase 8, fractalkine, IL-2, signaling lymphocytic activation molecule (SLAM), T cell surface glycoprotein CD8 isoform, TNF ligand superfamily member 14, and TNF receptor superfamily member 9 (TNFRSF9) and SLE occurrence.(P<0.05). Among 28 immune features analyzed, Nine and nineteen exhibited a positive and negative causal relationship with SLE. When selecting the inflammatory factors with the most significant P-values and 28 immune features in the MR analysis. IL-2 levels was significantly associated with increased SLE risk ( P = 0.029, β = 0.41, OR = 1.508, 95% CI = 1.040–2.185). Total effect of IL-2 levels on SLE was 0.410, The breakdown of this effect yielded an indirect effect of 0.024, mediated through the percentage of CD25 ^hi CD45RA ⁻ CD4 ⁺ Tregs, and a direct effect of 0.386 with a mediation rate of 6.05%. MR-Egger intercept test showed that there was no significant horizontal pleiotropy (P > 0.05) among the IVs. Sensitivity analysis supported the validity of the analysis. Conclusions These study exhibited causal associations between Caspase 8, fractalkine, IL-2, SLAM, T cell surface glycoprotein CD8 isoform, TNF ligand superfamily member 14, and TNFRSF9 and the etiology of SLE. Immune features are probably involved in this process. Our study suggested that IL-2 may mediated through new regulatory mechanism and may likely be potential therapeutic targets for SLE.