Infection with the viruses that cause cold sores, or herpes simplex (HSV), or shingles, or varicella-zoster (VZV), may be associated with aquaporin-4 (AQP4)-antibody-positive (AQP4-ab-positive) neuromyelitis optica spectrum disorder (NMOSD), according to a Mendelian randomization (MR) study published in the European Journal of Neurology.

Single nucleotide polymorphisms (SNPs) were identified for shingles and cold sore infections using genome-wide association study (GWAS) summary statistics from the 23andMe cohort. The SNP for cold sores (rs885950 in the POU5F1 gene) was found to be significantly associated with AQP4-ab-positive NMOSD using 2-sample MR analysis (odds ratio (OR) 745.318; P <0.001).

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Shingles infection was also found to be significantly associated with AQP4-ab-positive NMOSD (OR 21.073; P <0.001). A total of 3 SNPs were identified that were related to shingles including rs2523591 in the HLA-B gene, rs7047299 in the IFNA21 gene, and rs9260809 in the MICD gene. Only rs2523591 (P =0.027) and rs9260809 (P =0.003) were significantly associated with AQP4-ab-positive NMOSD using individual SNP analyses, however.

SNPs were identified for a total of 17 infections including hepatitis B, pneumonia, mononucleosis, mumps, plantar warts, tuberculosis, bacterial meningitis, scarlet fever, urinary tract infection frequency, myringotomy, strep throat, tonsillectomy, and chicken pox. None of these reached statistical significance with AQP4-ab-positive NMOSD during MR analyses, however. None of the SNPs, including those for cold sores and shingles, reached statistical significance for association with AQP4 antibody-negative NMOSD either.

“In conclusion, these findings suggested the positive associations between cold sores, shingles, and AQP4-ab-positive NMOSD, indicating there may be causal relations between HSV, VZV infection, and AQP4-ab-positive NMOSD. Further elucidation of the causality could provide insight into the potential biological roles of cold sores and shingles in the pathogenesis of AQP4-ab-positive NMOSD,” the authors wrote.

A total of 215 patients with NMOSD (132 AQP4-ab-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls of European descent were identified from the 23andMe cohort GWAS.


Wang L, Zhou L, ZhangBao J, et al. Causal relations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study. Eur J Neurol. Published online August 4, 2023. doi:10.1111/ene.16014