Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study

Abstract Background and purpose Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. Methods For data on infections, we used the genome‐wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti‐aquaporin‐4 antibody [AQP4‐ab]‐positive patients and 83 AQP4‐ab‐negative patients) and 1244 normal controls. Single‐nucleotide polymorphism (SNP) identification and two‐sample Mendelian randomization (MR) analyses were then performed. Results In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA‐B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA‐B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4‐ab‐positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [ p < 0.001, Q < 0.001]). The association between shingles and AQP4‐ab‐positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [ p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4‐ab‐positive or AQP4‐ab‐negative NMOSD. Conclusion These findings suggest there are positive associations between cold sores and shingles and AQP4‐ab‐positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella‐zoster virus infection and AQP4‐ab‐positive NMOSD.