Dissecting the Causal Pathway from Herpes Zoster to Postherpetic Neuralgia: A Multi-Stage Mendelian Randomization Study Implicating VZV-Specific IgE and Cerebrospinal Fluid Metabolites

Jianjin Zhang,1,* Yanhong Chen,1,* Xingyu Li,2,* Chaobo Feng,1 Jiapeng Li,1 Zhouyang Hu,1 Guoxin Fan,1 Xiang Liao1 1National Key Clinical Pain Medicine of China, Shenzhen Nanshan People’s Hospital, Shenzhen University Medical School, Shenzhen, 518052, People’s Republic of China; 2School of Medicine, Zunyi Medical University Zhuhai Campus, Zhuhai, 519041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang Liao; Guoxin Fan, National Key Clinical Pain Medicine of China, Shenzhen Nanshan People’s Hospital, Shenzhen University Medical School, No. 89 Taoyuan Road, Nanshan District, Shenzhen, Guangdong Province, 518052, People’s Republic of China, Email liaoxiang75@email.szu.edu.cn; fanguoxin@email.szu.edu.cnBackground: Postherpetic neuralgia (PHN) develops in 10– 20% of herpes zoster (HZ) patients, yet the causal mechanisms driving this transition from acute infection to chronic neuropathic pain remain elusive. VZV-specific immunoglobulin E (IgE) and cerebrospinal fluid (CSF) metabolites represent candidate intermediate phenotypes that may mediate neuroimmune dysfunction, but their sequential causal relationships remain unexplored. We hypothesized that IgE and CSF metabolites constitute a hierarchical causal pathway from HZ exposure to PHN risk.Methods: We conducted a multi-stage Mendelian randomization study. First, two-sample Mendelian Randomization (MR) with MRlap correction established causal effects of HZ on IgE and screened 435 CSF metabolites for PHN associations. Given substantial HZ-PHN sample overlap precluding total effect estimation, multivariable MR (MVMR) evaluated whether metabolites mediate IgE effects on PHN.Results: HZ exhibited a significant causal effect on VZV-specific IgE (IVW: β = 0.237, 95% CI: 0.104– 0.371, P = 4.95× 10− 4). Among 435 metabolites, two showed effects significant after FDR correction: 1-stearoyl-2-oleoyl-GPC (β = 2.448, FDR-adjusted P = 0.043) and N-methylproline (β = − 0.425, FDR-adjusted P = 0.046). Critically, 5-methyluridine—nominally significant in univariable analysis (P = 0.095)—demonstrated a robust independent protective effect in MVMR (MV-IVW: β = − 3.227, 95% CI: − 5.765 to − 0.688, FDR-adjusted P = 0.025; OR = 0.040). The IgE→PHN effect attenuated to non-significance (P = 0.202) upon adjusting for 5-methyluridine, consistent with metabolic mediation.Conclusion: These findings support a sequential causal pathway from HZ to PHN involving IgE and CSF metabolites, identifying 5-methyluridine as a potential modifiable protective factor and highlighting neuroimmune-metabolic crosstalk in chronic pain pathogenesis.Keywords: Mendelian randomization, postherpetic neuralgia, herpes zoster, VZV-specific IgE, cerebrospinal fluid metabolites, 5-methyluridine