S1-S7 Tables are included in the file.

BackgroundObservational studies have suggested a relationship between type-1 diabetes mellitus (T1DM) and systemic lupus erythematosus (SLE). In both autoimmunities, 25-hydroxyvitamin D (25-OHD) deficiency is common. However, the causality between T1DM, 25-OHD level and SLE remains largely unknown.MethodsIndependent genetic variants associated with T1DM, 25-OHD level, and SLE from the largest genome-wide association studies were used to conduct two-sample bidirectional Mendelian randomization (BIMR) and two-step Mendelian randomization (MR) analysis to estimate causal relationship between T1DM, 25-OHD level and SLE, and further multivariable Mendelian randomization (MVMR) was used to verify direct causality of T1DM and 25-OHD level on SLE. A series of sensitivity analysis as validation of primary MR results were performed.ResultsConsistent with the results of BIMR, there was strong evidence for a direct causal effect of T1DM on the risk of SLE (ORMVMR-IVW = 1.249, 95% CI = 1.148–1.360, PMVMR-IVW = 1.25×10−5), and 25-OHD level was negatively associated with the risk of SLE (ORMVMR-IVW = 0.305, 95% CI = 0.109–0.857, PMVMR-IVW = 0.031). We also observed a negative causal effect of T1DM on 25-OHD level (ORBIMR-IVW = 0.995, 95% CI = 0.991–0.999, PBIMR-IVW = 0.030) while the causal effect of 25-OHD level on the risk of T1DM did not exist (PBIMR-IVW = 0.106). In BIMR analysis, there was no evidence for causal effects of SLE on the risk of T1DM and 25-OHD level (PBIMR-IVW > 0.05, respectively).ConclusionOur MR analysis suggested that there was a network causal relationship between T1DM, 25-OHD level and SLE. T1DM and 25-OHD level both have causal associations with the risk of SLE, and 25-OHD level could be a mediator in the causality of T1DM and SLE.