CrowdSpeak & ResearchSpeak: EBV and the genetic risk of MS

Could EBV interact with genes that predispose you to getting MS? #MSResearch #CrowdSpeak #CrowdacureMS

"I would like to thank those of you who donated money to our Crowdfunding project; it is much appreciated. If you haven't donated yet please consider doing it. The research we are doing will allow us finalise the power calculations to find the correct dose of anti-EBV drug we plan to use in the ARTEMIS study. If you recall you helped design and name this study and some of you recommended we use crowdfunding to get this project off the ground. We therefore view this experiment, the fund raising and the ARTEMIS study, as enabling the crowd."

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"We refer to MS as being a complex disease; i.e. a disease that occurs due to an interaction between your genes and the environment. This doesn't exclude one environmental factor as being pivotal in the causal pathway, in other words if that factor is absent you won't get MS. This is why the observation that MS does not occur in people who don't have EBV is so important. There are some studies who have described a small number of pwMS who are EBV negative, however, most of these studies have used simple antibody, or serological, assays to assess EBV positivity. When you limit the analysis to studies using more than one technique to assess EBV infection positivity rates are 100%. This is why many of us in the field are very keen to get an EBV vaccination study off the ground to  test whether by preventing EBV infection we can prevent MS. Unfortunately, we don't have a protective EBV vaccine at present. I am hopeful this will change in the near future. I am aware that the NIH are working on a new EBV vaccine."

"Could EBV be associated with MS by interacting with the main genetic MS susceptibility genes? The meta-analysis below looks at the interaction between EBV infection and the presence of the main susceptibility gene (HLA-DRB1*1501). The authors find that there is a minor interaction between them; in statistical speak this interaction is additive and not multiplicative. My problem with this meta-analysis is that it includes data from studies that have determined the presence, or absence, of EBV infection with simple serological studies. In other words the pwMS who are EBV-negative in these studies are likely to be EBV-positive if they were tested using more sensitive techniques."

"Another obvious question to ask is: could the link between infectious mononucleosis (IM) and MS be explained by genetic factors, in other words do the genes that increase your susceptibility to getting MS simply increase your chances of getting IM? We looked at this several years ago and excluded this possibility in relation to the main genetic risk factor HLA. Therefore it looks as if the link between IM and MS cannot simply be explained by a common genetic factor."

"Based on these and other observation we hypothesise that there must be something specific to the biology of EBV that will explain how it triggers and/or drives MS. This is the main reason why we set-up the Charcot Project." 

Xiao et al. A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis. Sci Rep. 2015 Dec 11;5:18083. doi: 10.1038/srep18083.

Background: Infection with Epstein-Barr virus (EBV) and HLA-DRB1*1501-positivity is a risk factor for multiple sclerosis (MS), but whether an interaction between these two factors causes MS is unclear. 

Objective: We therefore conducted a meta-analysis on the effect of the interaction between HLA-DRB1*1501 and EBV infection on MS. 

Methods: Searches of PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and the Wanfan databases through February 2015 yielded 5 studies that met the criteria for inclusion in the meta-analysis. EBV infection and HLA-DRB1*1501-positivity were dichotomized. The additive (S) and multiplicative interaction indexes (OR) between EBV infection and HLA-DRB1*1501 and their 95% confidence intervals (95%CI) were calculated for each study and then combined in a meta-analysis. 

Results: EBV infection was significantly associated with MS (OR = 2.60; 95%CI, 1.48-4.59). HLA-DRB1*1501 was associated with a significantly increased risk of MS (OR, 3.06; 95%CI, 2.30-4.08). An interaction effect between EBV infection and HLA-DRB1*1501 on MS was observed on the additive scale (S, 1.43; 95%CI, 1.05-1.95, P = 0.023), but no interaction effect was observed on the multiplicative scale (OR, 0.86, 95%CI, 0.59-1.26). 

Conclusion: This meta-analysis provides strong evidence that EBV alone, HLA-DRB1*1501 alone or their interaction is associated with an elevated risks of MS.

CoI: Team G will be recipients of a grant from Crowdacure to perform this research

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