Vitamin D Links Genetic and Environmental Risk Factors in Multiple Sclerosis The risk to develop multiple sclerosis (MS) is well known to be co-defined by genetic and environmental factors. Possession of the major histocompatibility complex (MHC) allele HLA-DRB1*1501 represents by far the strongest genetic risk factor, while much smaller contributions are made by a range of other genes. Still, even this HLA-DRB1*1501 gene explains only a small part of the MS risk. Environmental factors are also relevant to the MS risk, and these factors notably include vitamin D levels, which are influenced both by diet and sunlight exposure. Low levels of vitamin D increase the MS risk. It now emerges that vitamin D levels and MHC are more intimately linked that previously appreciated. Not only does this start to explain much more of the MS risk, it also brings new life to the idea of using vitamin D as a therapeutic compound in MS. Epidemiological evidence for an effect of sunlight and vitamin D levels on the MS risk has been accumulating for many years. The geographical distribution of MS, being more prevalent in less sunny areas, is consistent with a protective effect of sunlight-induced vitamin D. Migrant studies tell the same tale. The more recently established effect of birth month points in the same direction. In the northern hemisphere people born in spring have a somewhat higher risk to develop MS than people born in autumn. Seasonal fluctuations in maternal levels of vitamin D during pregnancy could well account for this bias. Direct assessment of serum levels of vitamin D in relapsing-remitting MS patients confirms that they are generally lower than in healthy control subjects, with the most prominent difference occurring at the time of a clinical relapse. These apparently protective effects of vitamin D may in part relate to its anti-inflammatory effects. In animal models of neuroinflammation, vitamin D mitigates clinical disease. In cell culture models, it stimulates production of the anti-inflammatory mediator interleukin-10, and the development of regulatory T cells which control autoimmune responses. This even appears to be a self-amplifying effect, since vitamin D promotes expression of the vitamin D receptor itself. Now, as it turns out, vitamin D also influences the expression of HLA-DRB1*15, the major genetic risk factor in MS. While it remains to be established what exactly the mechanisms might be by which altered expression of the HLA-DRB1*1501 haplotype exerts an effect on the development of MS, the mere fact that its expression is linked to vitamin D levels uncovers a critical link between environmental factors and genetic risk factors. Such a link may well explain the somewhat confusing data that have accumulated on the MS risks in twins. While the concordance rate of MS among identical twins in Canada is close to 30%, it is only around 14% in Italy. Not only has it remained puzzling why these twin data would be so different in different geographical areas, it has also remained obscure why concordance rates between identical twins are so much higher than between non-identical twins, or other family members for that matter. The idea that co-operative effects by multiple genes would account for this has not found support from genome-wide association studies, which have revealed only very weak genetic effects by any other gene than HLA-DRB1*1501. A co-operative effect between this gene and maternal vitamin D levels during pregnancy and the first years of life, on the other hand, now becomes a more attractive explanation. After all, identical twins share this factor, while non-identical twins do not. The effects of vitamin D, and its link with the genetic MS risk, clearly raise the question whether or not vitamin D could be used as a therapeutic compound to control MS, or even more intriguing, to prevent it. Studies of vitamin D levels in young children have suggested that in the years before MS starts to become apparent, vitamin D levels are markedly lower in those children that go on to develop MS. Along with the month-of-birth effect, this makes a strong case to stimulate anyone to maintain healthy levels of vitamin D, especially early in life. This may not just help reduce the incidence of MS, but of other disorders as well. The question whether vitamin D can be used to slow down MS once it has already started, is another. Some evidence suggests that it might, and the option to do so is too attractive to ignore. Yet, high levels of vitamin D pose well-known risks to calcium metabolism. Caution is therefore required in exploring the use of high doses of vitamin D as a disease-modifying strategy in MS. More is not always better. At this point in time, however, all the evidence argues in favor of at least trying.