Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors

Background: Epstein-Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. Methods: Pubmed was searched using the terms 'multiple sclerosis' AND 'Epstein Barr virus', 'multiple sclerosis' AND EBV, 'clinically isolated syndrome' AND 'Epstein Barr virus' and 'clinically isolated syndrome' AND EBV. All abstracts were reviewed for possible inclusion. Results: A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 x 10(-4)). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. Conclusion: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.