Mendelian Randomization Identifies CD25+ CD4+ Tregs and Plasma Proteins in Androgenetic Alopecia Pathogenesis

Androgenetic alopecia (AGA) is a chronic form of hair loss influenced by various factors, with increasing focus on the role of immune cell-driven follicular microinflammation. However, the precise immune phenotypes involved and their causal relationship with AGA remain poorly understood. This study aims to identify and validate the causal role of immunophenotypes in AGA using Mendelian randomization (MR) integrated with multi-omics data, and to explore the mediating role of plasma proteins in this relationship.

We utilized publicly accessible Genome-Wide Association Studies (GWAS) summary statistics encompassing immune phenotypes, plasma proteins, and AGA. MR analyses using inverse variance weighted (IVW), MR-Egger regression, and weighted median methods were performed to examine the causal links between 731 immune phenotypes and AGA. Sensitivity analyses were conducted to ensure robustness and address heterogeneity and pleiotropy. Linkage disequilibrium score regression was employed to assess genetic correlations, while Steiger filtering confirmed the causal direction. A multivariable MR approach was used to estimate the direct effects of each exposure on AGA, accounting for confounding factors. Additionally, mediation analysis of 3622 plasma proteins identified potential mediators in the immune-AGA pathway.

We identified elevated CD25 on secreting CD4 regulatory T cell (Treg) as an independent genetic risk factor for AGA. Mediation analysis revealed five plasma proteins, SDF-1, GPIbα, KIR3DS1, MVI, and WFDC5, as key mediators in the immune-AGA axis.

This study established that specific immune cell phenotypes, particularly CD25 on secreting CD4 Treg, were causally linked to AGA, with plasma proteins mediating this effect. These findings provide new insights into AGA's immunological mechanisms and suggest potential immune-targeted therapeutic strategies.