Bidirectional Mendelian Randomization Suggests Causal Effects of 731 Immunophenotypes on Vitiligo Pathogenesis

Purpose: This two-sample Mendelian randomization (MR) study aimed to investigate the causal relationship between 731 immune cell traits and vitiligo. Patients and Methods: Genetic variants with genome-wide suggestive significance ( P < 1× 10 − 5 ) were used as instrumental variables (IVs). Immune phenotype data were sourced from 3757 European individuals (SardiNIA study), while vitiligo data included 385,538 samples (292 cases, 385,509 controls) from FinnGen (Release 9). Primary causal inference utilized inverse-variance weighted (IVW) regression, supplemented by weighted median, mode-based, and MR-Egger methods for sensitivity analyses. Horizontal pleiotropy and heterogeneity were assessed via MR-Egger intercept and Cochran’s Q tests. False discovery rate (FDR) correction was applied, with PFDR < 0.05 considered significant and PFDR < 0.20 considered suggestive. Results: The onset of vitiligo was significantly associated with reduced levels of TD CD4 + %T cells (OR = 0.63, 95% CI: 0.51– 0.78; PFDR = 0.015, significant) and showed a suggestive association with decreased CD4 expression on HLA DR + CD4 + cells (OR = 0.65, 95% CI: 0.50– 0.85; PFDR = 0.166, suggestive). Conversely, suggestive evidence was found for an association between vitiligo and increased CD28 expression on CD28 + CD45RA + CD8br cells (OR = 1.37, 95% CI: 1.13– 1.65; PFDR = 0.166, suggestive) and with elevated CD8 expression on EM CD8br cells (OR = 1.46, 95% CI: 1.19– 1.79; PFDR = 0.091, suggestive). Sensitivity analyses confirmed robustness ( P pleiotropy > 0.05). Conclusion: We suggest novel causal links between vitiligo and specific immune cell dysregulation, highlighting the pivotal role of adaptive immunity in pathogenesis and informing potential therapeutic targets such as TD CD4 + T cells and CD8 + T cell subsets. Keywords: vitiligo, mendelian randomization, immune phenotyping, autoimmunity, causal inference