Investigation of the Causal Association Between Treg Cells and Actinic Keratosis Through Two-Sample Mendelian Randomization Analysis.

Purpose: Actinic keratosis is a highly prevalent precancerous skin condition and a major risk factor for cutaneous squamous cell carcinoma with a significant risk of malignant transformation. Despite its clinical importance, the causal role of immune factors, especially regulatory T (Treg) cells, in actinic keratosis pathogenesis remains unclear. A two-sample Mendelian Randomization (MR) approach was employed to investigate the potential causal link between distinct characteristics of Treg cells and the likelihood of developing actinic keratosis. Patients and Methods: The analysis utilized publicly available genetic data on 167 Treg cell traits and actinic keratosis risk. The Inverse Variance Weighted (IVW) method was the primary analytical approach, supported by MR-Egger, weighted median, and weighted mode analyses. Sensitivity of the findings was assessed through Cochran's Q test, MR-Egger analysis, the MR pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out tests. Results: The IVW analysis revealed a significant association between resting Treg cell activity and actinic keratosis (OR: 0.9997, p = 0.0420). Additional significant associations included CD39+ resting Treg percentage of CD4 Tregs (OR: 0.9998, p = 0.0123), CD28- double negative (DN) Treg percentage (OR: 0.9995, p = 0.0359), and CD28+ CD45RA- CD8dim Tregs (OR: 1.0002, p = 0.0312). No significant associations were found in supplementary analyses, but sensitivity tests confirmed the reliability of the results. Conclusion: This study suggests a potential causal relationship between certain Treg cell traits and the risk of actinic keratosis, indicating that further research is needed to clarify the underlying mechanisms of this association.