Multiple sclerosis: the environment and causation

PURPOSE OF REVIEW: We review current thinking on the aetiology of multiple sclerosis, how genetic susceptibility interacts with environmental risk factors at the population level, multiple sclerosis-associated risk factors and contemporary causation theory. RECENT FINDINGS: Two large genomic studies have confirmed the unambiguous associations with the DRB1 and DQB alleles of the human leucocyte antigen class II region. No other region with genome-wide significance has been identified. Family-based genetic epidemiological approaches have found no evidence of nongenetic transmissibility. This indicates that the action of the environment in influencing multiple sclerosis risk is operative at a macroenvironmental or population level, and not within families or the microenvironment. Environmental factors receiving renewed attention include vitamin D status, Epstein-Barr virus infection and smoking. Bradford Hill's criteria for causation have been modified and should be adopted as a framework for demonstrating causation in relationship to multiple sclerosis. SUMMARY: Multiple sclerosis is a complex disease because of interaction between genes and the environment. Any theory of causation for a specific agent will have to be congruent with the biology of the disease.