Negative interaction between smoking and infectious mononucleosis in the risk of MS

Epstein-Barr virus (EBV), low levels of vitamin-D, smoking and the haplotype containing HLA-DRB1 have consistently been shown to be associated with an increased risk of MS. However, only modest associations have been found. An attractive hypothesis is that interactions between these factors may help to explain the variation in risk. We studied evidence of interaction between smoking and a history of infectious mononucleosis (IM, as a proxy for EBV) in a large multinational case-control study including subjects from Italy, Norway, Sweden, Serbia and Canada (EnvIMS). Analyzing currently included 2125 cases and 4455 controls we found that both IM and smoking, individually, were important factors in all countries included. Adjusted for age and sex the pooled odds ratio (OR) was 2.0 (95% CI: 1.6-2.4) for IM and of 1.8 (95% CI: 1.6-2.4) for smoking. We found that the effect of IM was significantly higher among non-smokers, pooled OR of 2.4 (95% CI: 1.8-3.2), than among smokers, pooled OR of 1.6 (95% CI: 1.3-2.1), p-value = 0.04 using multiplicative interaction term in logistic regression. This negative interaction was found in all countries included and among men and women separately. While the case-control design has limitations related to the retrospective ascertainment of risk factors, it is unlikely that the negative interaction in this study could be the result of recall bias. This observation does not support the hypothesis that the risk of MS related to EBV is increased by the presence of smoking. Indeed, our results are consistent with the suggestion that EBV (as measured by IM) and smoking represent different pathogenic pathways in MS.