Mendelian randomisation is a research method that uses genetic variation as a natural experiment to test whether a relationship between a risk factor and an outcome is causal rather than just a correlation…in other words it is a cheap way of generating loads of papers for not alot of effort:-).
There have been studies suggesting that antibodies against EBV notably EBNA-1 cross react and cause multiple sclerosis and other conditions this looks at MS and other conditions and concludes that the data on which the idea that antibodies to EBNA-1 as a cause is suggestive but abit dogey, which I guess we have thought since it was first muted as the findings are not reproducible and here they say antibodies to ZEBRA are protective.
So what is ZEBRA?
Zebra BamHI Z Epstein-Barr virus replication activator), also known as Zta or EB1, is a 27 kDa transcription factor encoded by the EBV BZLF1 gene.. It acts as a critical molecular switch that triggers the Epstein-Barr virus (EBV) to switch from a dormant (latent) life cycle to a productive (lytic) phase, initiating viral replication and disease progression. So does this mean if you stop EBV becoming active it is protective
The vaccine developers are worried that they will make MS worse and that is perhaps understandable if vaccination produced antibodies and the great and the good tell us they are a bad thing as the cause MS as opoosed to getting rid of EBV. But if the antibodies where protective noow you are talking.
Sun S, Wen Y, Tang P, Xie F, Ding T, Wen J, Xu A. Causal effects of Epstein-Barr virus antibodies on autoimmune neuroinflammatory diseases: A generalised summary data-based Mendelian randomisation study. Medicine . 2026;105(15):e48264.
Observational studies associate Epstein-Barr virus (EBV) with multiple sclerosis (MS), but causality across autoimmune neuroinflammatory diseases (ANDs) remains uncertain. This study aimed to assess the causal effects of 5 EBV antibodies…..using Mendelian randomization (MR). Genetic instruments for EBV antibodies (anti-EBNA-1, VCA p18, ZEBRA, EA-D, IgG) were sourced from UK Biobank (UKB). Outcome data…..were from FinnGen (discovery), UKB, and International Multiple Sclerosis Genetics Consortium (replication). Applying an evidence-tiered interpretation, we found a high-confidence, protective causal effect of increased ZEBRA antibody levels on MS risk (odds ratio [OR] = 0.705, P = 2.967 × 10-6), which was robust to multiple testing nominally supported in an independent cohort (IMSGC). In contrast, the association between EBNA-1 antibodies and increased MS risk (OR = 1.284, P = 2.450 × 10-4) was graded as suggestive as it showed nominal support only in one of 2 validation cohorts (UKB) and was substantially attenuated after excluding HLA-region single nucleotide polymorphisms, indicating shared genetic architecture rather than direct causation. ….This study provides high-confidence genetic evidence for a protective role of ZEBRA antibodies in MS, which was robust to multiple testing and nominally supported in an independent cohort [International MS Genetics Consortium (IMSGC)], and suggestive evidence for an HLA-mediated link between EBV-encoded nuclear antigen-1 (EBNA-1) and MS which showed nominal support only in one of 2 validation cohorts.
But Hang-On if it is easy pickings and there alot of people in the land of mendelian randomisation studies in MS then this would have been done. Guess what
Huang L, Han L, Lin Q. Bidirectional causal relationships between antibody-mediated immune responses and autoimmune diseases: Insights from Mendelian randomization analysis. Medicine. 2026 Jan 2;105(1):e47013.
Autoimmune diseases like systemic lupus erythematosus (SLE) and multiple sclerosis (MS) involve intricate interactions between immune responses and genetic factors, and this study aimed to explore the causal and bidirectional relationships between antibody-mediated immune responses and these diseases to deepen understanding of their mechanisms. A bidirectional 2-sample Mendelian randomization (MR) approach was used, with genetic variants as instrumental variables; antibody data were obtained from the UK Biobank, and from the FinnGen database. (Sound familiar). The results showed that elevated levels of Epstein-Barr virus EBNA-1 and ZEBRA antibodies were associated with a reduced risk of SLE…For MS, higher Epstein-Barr virus EBNA-1 antibody levels were linked to an increased risk Bidirectional analyses revealed that autoimmune diseases such as SLE and MS also affect antibody levels, indicating a complex 2-way interaction. This study identifies the bidirectional relationships between antibody-mediated immune responses and autoimmune diseases, notes that pathogen-specific antibody levels can act as protective or risk factors depending on the disease, and provides new insights into the immunopathogenesis of SLE and MS as well as potential directions for therapeutic intervention.
For MS, GSMR analysis identified a positive association between EBV EBNA-1 antibody levels and increased risk (OR = 1.266, 95% CI: 1.103–1.453, P = 7.98 × E–04, FDR = 0.018), which was corroborated by conventional 2-sample MR results (OR = 1.650, 95% CI: 1.141–2.386, P = .008).
So what happened with ZEBRA in this study?
Source: multiple-sclerosis-research.org