Causal Effects of Herpesvirus-Associated Antibodies on Autoimmune neuroinflammatory diseases: Mendelian Randomization Study

Abstract Background Herpesvirus infections may trigger Autoimmune neuroinflammatory diseases (ANDs), but their causal role is uncertain. This study used Mendelian randomization (MR) to investigate the causal effects of herpesvirus antibodies on ANDs. Methods We assessed 22 herpesvirus antibodies and five ANDs—multiple sclerosis (MS), neuromyelitis optica (NMO), myasthenia gravis (MG), Guillain-Barr é syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP)—using five MR methods. MR-PRESSO, MR-Egger, and Cochran’s Q statistic identified pleiotropy and heterogeneity. Bonferroni correction set the significance threshold at P<4.545e-04. Validation used UK Biobank and FinnGen data, with meta-analysis for inconsistent results. Results Significant positive causal effects were found for Epstein-Barr virus encoded nuclear antigen-1 (EBV EBNA-1) (OR=3.009), EBV viral capsid antigen (VCA) p18 (OR=8.700), and human herpesvirus 7(HHV7) U14 (OR=3.359) antibody levels on MS risk, and HHV7 U14 (OR=10.641), Varicella zoster virus glycoprotein E and glycoprotein I(VZV gE and gI) (OR=17.220) antibody levels on NMO risk. VZV gE and gI (OR=2.542) antibodies increased MG risk, while EBV ZEBRA (OR=0.592)reduced MS risk. Negative effects of EBV EA-D and ZEBRA antibodies on NMO were also noted. Validation confirmed the effects of EBV EBNA-1, EBV VCA p18 antibodies on MS, and VZV gE and gI on antibody MG, while EBV ZEBRA and HHV7 U14 antibodies effects on MS were not validated. Conclusions The study suggests a causal link between specific herpesvirus antibodies and the risk of MS, NMO, and MG.