Causal Impact of Blood Cell Traits on the Risk of Herpes Zoster: A Two-Sample Mendelian Randomization Study Based on Exogenous Stimulation Data

Background: Herpes zoster (HZ) is a common neurotropic infectious disease caused by the reactivation of varicella-zoster virus (VZV), primarily triggered by declining host immune function. While circulating immune cells play key roles in antiviral defense, the causal contributions of distinct blood cell functional phenotypes to HZ risk remain unclear. Objective: To investigate potential causal associations between genetically predicted blood cell functional traits under ex vivo stimulation and the risk of HZ using a two-sample Mendelian randomization (MR) framework. Methods: We employed genome-wide association analysis summary statistics of 91 stimulation-induced blood cell traits published in 2024 as exposures, and HZ outcome data from the FinnGen R12 release (7,132 cases and 480,316 controls). The inverse variance weighted method was used for primary causal inference, complemented by alternative MR approaches and sensitivity analyses to assess robustness. No formal multiple testing correction was applied due to a single significant result. Results: Among 85 eligible traits, the forward scatter standard deviation (FSC-SD) of red blood cells under nigericin stimulation was significantly associated with increased HZ risk (OR = 1.13, 95% CI: 1.06–1.20, p = 1.02 × 10 −4 ). No other traits reached nominal significance. Sensitivity analyses revealed no evidence of horizontal pleiotropy or heterogeneity. Conclusion: This study provides novel genetic evidence that nigericin-induced red blood cell membrane stress responses, operating through NLRP3-dependent inflammatory cascades, are causally linked to VZV reactivation susceptibility. The nigericin-stimulated red blood cells FSC-SD phenotype may serve as a functional biomarker for viral reactivation risk stratification and individualized immune monitoring.