Causal relationship between genetically predicted white blood cell count and systemic lupus erythematosus

Observational studies have suggested an association between white blood cell (WBC) count and systemic lupus erythematosus (SLE). However, the causal relationship remains uncertain because of potential confounding factors. This Mendelian randomization (MR) study aimed to investigate the causal effect of WBC count on SLE risk by using genetic instruments. Genetically predicted higher WBC counts were associated with a reduced risk of SLE (inverse-variance weighted [IVW]: odds ratio = 0.384, 95% confidence interval = 0.160–0.920, P = .031; weighted median: odds ratio = 0.326, 95% confidence interval = 0.124–0.859, P = .023). MR-Egger regression revealed no evidence of horizontal pleiotropy (intercept, P = .705), and MR polygenic residual sum and outlier (MR-PRESSO) detected 4 outliers. After outlier removal, heterogeneity decreased, and the IVW and weighted median estimates remained significant (beta = −0.96, P = .03; beta = −1.12, P = .023, respectively). We conducted a 2-sample MR analysis using summary statistics from genome-wide association studies (GWAS) of European ancestry: WBC count (GWAS ID: ieu-b-30, N = 563,946) and SLE (GWAS ID: ieu-a-815, 14,267 cases, and 43,047 controls). Sixty-five independent single-nucleotide polymorphisms ( P < 5 × 10 −8 , clumped at r 2 < 0.001) were selected as instrumental variables, with a mean F statistic of 28.6, indicating strong instrument strength. Analyses were performed using R statistical software (R Foundation for Statistical Computing) with the TwoSampleMR and MR-PRESSO packages. The primary analytical methods included IVW, weighted median, and MR-Egger regression. Sensitivity analyses included Cochran Q test for heterogeneity, MR-PRESSO outlier correction, and leave-one-out validation to ensure robustness. This MR analysis supports an independent causal protective effect of genetically predicted higher WBC counts on SLE risk. These findings should not be extrapolated as evidence for therapeutic leukocyte elevation, nor do they alter the clinical management of leukopenia observed in active SLE or during immunosuppressive therapy. The genetic signal likely reflects broader immune homeostatic regulation rather than lineage-specific effects, the mechanistic basis of which warrants dedicated functional investigation.