The epidemiology of multiple sclerosis: insights to a causal cascade.

MS-pathogenesis involves both genetic-susceptibility and environmental determinants. Three (or more) sequential environmental-factors are implicated. The first acts near birth, the second acts during childhood/adolescence, and the third acts subsequently. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem particularly well-suited to the first two environmental-events but other factors (e.g., obesity and smoking behavior) seem also to be involved in the causal scheme. MS-pathogenesis can be modeled by incorporating both the environmental and genetic-factors into a causal scheme, which can then help to explain some of the changes in MS-epidemiology (e.g., increasing disease-prevalence, changing sex-ratio, and regional-variations in monozygotic-twin-concordance-rates), which have been taking place recently. This model suggests that genetic-susceptibility is overwhelmingly the most important determinant of MS and that, at least, 92.5% of individuals (and likely much more) are, essentially, incapable of developing MS, regardless of their specific environmental-exposures. Nevertheless, the genetics is complex and the contribution of any specific gene to MS-susceptibility seems to be quite modest. Thus, even for the DRB1*1501 allele (the strongest known MS-susceptibility marker), most carriers are not in the genetically-susceptible group. Moreover, 45-50% of individuals with MS lack this allele entirely and some of the haplotypes that carry this allele don't also confer any disease-risk. Finally, because the prevalence of genetic-susceptibility seems to be so similar throughout North America and Europe, and despite the crucial importance of a person's genetic make-up to disease pathogenesis, it is the environmental-factors, which largely responsible for the observed regional variations in disease-characteristics. Thus, despite MS being more common in women, men are more likely to be genetically-susceptible. This apparent paradox seems to relate to the fact that women are much more responsive than men to the recent changes in environmental-exposure (whatever these have been). These gender-differences may help to explain changes in the sex-ratio and the increasing disease-prevalence, which have both been observed recently. The potential importance of these conclusions regarding the role of environment in MS-pathogenesis is that they open the door to the possibility of pursuing strategies for primary primary disease prevention in the future.