Mendelian Randomization Analysis Suggests No Associations of Herpes Simplex Virus Infections With Multiple Sclerosis

Abstract

Previous studies have suggested an association between infection with herpes simplex virus (HSV) and liability to multiple sclerosis (MS), but it remains largely unknown whether the effect is causal. We performed a two-sample Mendelian randomization (MR) study to explore the relationship between genetically predicted HSV infection and MS risk. Genetic instrumental variables for diagnosed infections with HSV (p < 5 × 10–6) were retrieved from the FinnGen study, and single nucleotide polymorphisms associated with circulating immunoglobulin G (IgG) levels of HSV-1 and HSV-2 and corresponding summary-level statistics of MS were obtained from genome-wide association studies of the European-ancestry. Inverse-variance weighted MR was employed as the primary method and multiple sensitivity analyses were performed. Genetically proxied infection with HSV was not associated with the risk of MS (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.90–1.02; p = 0.22) per one-unit increase in log-OR of herpes viral infections. MR results provided no evidence for the relationship between circulating HSV-1 IgG levels and MS risks (OR = 0.91; 95% CI, 0.81–1.03; p = 0.37), and suggested no causal effect of HSV-2 IgG (OR = 1.04; 95% CI, 0.96–1.13; p = 0.32). Additional sensitivity analyses confirmed the robustness of these null findings. The MR study did not support the causal relationship between genetic susceptibly to HSV and MS in the European population. Further studies are still warranted to provide informative knowledge, and triangulating evidence across multiple lines of evidence are necessary to plan interventions for the treatment and prevention of MS.

Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus

“…With the exponential growth and widespread availability of genotype data, Mendelian randomization (MR) diminishes confounding, strengthens exposure‐outcome associations, and avoids the reverse causalities approach as an epidemiologic study designed to establish a basis between exposures and outcomes 23 . More importantly, the method has been used as a valid tool to study causal relationships of SLE or HSV with several other factors 24–27 …”

“…23 More importantly, the method has been used as a valid tool to study causal relationships of SLE or HSV with several other factors. [24][25][26][27] We estimated the causality of these associations with twosample MR (TSMR) analysis by leveraging summary-level data from extensive genome-wide association studies (GWASs) of HSV infection and SLE risk. It has been reported that only IgG and its Fc portion showed an increased binding rate to HSV-infected cells compared to the uninfected control cells, and other structurally related beta2 microglobulin and other human immunoglobulins like IgM did not exhibit any change in their levels.…”

Association Between Sleep Traits and Rheumatoid Arthritis: A Mendelian Randomization Study

“…MR adopts germline genetic variants as proxies. Because environmental factors and disease processes have no effect on genetic variants, MR can reduce the influence of other factors, enhance the exposure-outcome relationship, and remove reverse causality ( 20 ). It is thought to be a reliable method for circumventing the limits of observational studies by employing genetic variation as an instrumental variable and large-scale data from GWASs ( 21 ).…”

A systematic review of Mendelian randomization studies on multiple sclerosis

“…The causal involvement of HSV virus infection has been investigated by Zhang et al (2022), based on the hypothesis of its involvement in the pathogenesis of MS. HSV, in fact, could invade the CNS, and its presence was found in brain demyelinating plaques of MS patients by analysing post‐mortem tissue (Sanders et al, 1996). However, conflicting observational studies did not find any relationship between HSV infection and MS risk, such as Etemadifar et al (2019) and Koros et al (2014).…”