NMRAL1 as a Causal Factor in Postherpetic Neuralgia: A Proteome-Wide Mendelian Randomization Study

Hong Ye,1,* Yiling Wang,2,* Yuechun Shi,1 Yuyu Wu,1 Qiuhan Xu,2 Songmin Huang1 1Xiangshan Hospital of TCM Medical and Health Group, Ningbo City, Zhejiang Province, People’s Republic of China; 2School of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiuhan Xu, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310000, People’s Republic of China, Email [email protected]; Songmin Huang, Xiangshan Hospital of TCM Medical and Health Group, Ningbo, Zhejiang Province, 315700, People’s Republic of China, Email [email protected]: Postherpetic neuralgia (PHN) is a chronic pain condition following herpes zoster infection, disproportionately affecting elderly and immunocompromised individuals. Despite its significant clinical impact, the underlying mechanisms of PHN remain exclusive, and effective treatments are limited. Circulating plasma proteins offer insights into PHN pathogenesis and serve as potential biomarkers or therapeutic targets.Methods: We analyzed FinnGen R12 GWAS data (490 PHN cases and 435,371 controls) and protein quantitative trait loci (pQTL) data for 4907 plasma proteins from 35,559 Icelanders. Mendelian randomization (MR) was conducted to investigate causal associations between plasma proteins and PHN risk. Causal effects were assessed using inverse variance weighting (IVW) and MR-Egger methods.Results: MR analysis identified NMRAL1 as the only plasma protein causally associated with PHN. Genetically predicted higher levels of NMRAL1 were linked to a reduced risk of PHN (IVW odds ratio = 0.553, 95% confidence interval: 0.405– 0.755, p = 0.000193). No evidence of heterogeneity or pleiotropy was observed, and sensitivity analyses, including leave-one-out analysis, confirmed the robustness of the findings. No other plasma proteins showed significant associations with PHN.Conclusion: This study identifies NMRAL1 as a protective factor for PHN and underscores its potential as a biomarker and therapeutic target. The findings highlight the utility of integrating proteomic and genetic data to advance understanding of complex neurological disorders like PHN.Keywords: postherpetic neuralgia, Mendelian randomization, novel protein biomarkers