Multiple sclerosis (MS) is an enigmatic and complex disease. Decades of studying the geographic and ethnic distribution of MS cases and familial clustering led to the realization that it has a multi-factorial cause incorporating both genetic and environmental factors. For example, family and twin studies showed that if one of a pair of identical twins developed the disease, the other twin had about a 25% chance of doing so, whereas fraternal twins had only a 2.5% concurrence rate. There must therefore be a genetic element to MS. But just as importantly, environmental components must also be involved: if genetics were the whole story for MS causation, the concurrence rate for identical twins would be 100%.

Recent genetic and epidemiological research has begun to pick the lock of the MS mystery. Following environmental clues, researchers consistently found that MS occurred more frequently in the temperate zones of both hemispheres, especially in northern Europe, the northern United States, southern Canada, southern Australia and New Zealand. Similar geographical patterns have also been noted for other inflammatory disorders and have stubbornly resisted detailed explanation.

These observations add strength to the hypothesis that MS is linked to some feature that correlates with latitude — in particular, with endogenous levels of vitamin D. After all, lower sunlight exposure among people living farther from the equator could limit the production of the vitamin D precursor in the skin.

Levels of vitamin D are maintained by a complex metabolic pathway influenced by both genetic traits and environmental factors, such as diet and sun exposure. Vitamin D precursors can be ingested in the diet or produced in the skin by sunlight. In either case, the precursor undergoes two different enzymatic modifications — one in the liver, the other in the kidney — to produce the active hormone. It seems plausible that lower cutaneous generation of vitamin D precursors could combine with reduced intake to produce a deficiency that increases the risk of developing MS. Of course, things are rarely as simple as they first seem — both epidemiological and animal-model studies now suggest that there is more to the effect of ultraviolet B (UVB) radiation than vitamin D levels. However, this insight never would have been gained without the initial discovery of the link between sunlight and vitamin D.

Other types of evidence also point towards this hypothesis. Prospective studies of two large cohorts of female nurses, followed for decades to determine how epidemiological factors related to disease, showed that low vitamin D levels predicted an increased risk of developing MS. But researchers studying other inflammatory autoimmune diseases and certain cancers have concluded that the actions of vitamin D extend far beyond bone health, regulating cell division and exerting strong effects on immune function4. These findings sparked additional studies showing that increasing or decreasing vitamin D levels could modify the severity of autoimmune animal models of MS. What is more, clinical studies showed that individuals with red hair and pale skin who avoided sunlight for fear of burning were found to be at increased risk for MS. Even in identical twins, differences in sunlight exposure affected susceptibility to developing MS.

The MS genetics community has been equally active in exploring the connection with vitamin D. Researchers applied increasingly powerful genetic tools to study larger and larger cohorts, producing an unprecedented depth of insight into the heritable underpinnings of the disease. Overwhelmingly, the strongest influence comes from a set of genes that govern how immune-system T lymphocytes 'see' structures derived from microbial pathogens. Each person's body recognizes these structures in a different way, helping to ensure that at least some members of a population will mount an effective response against new pathogens. These genes are also known to have a strong influence on autoimmunity and had long been associated with MS. Finding these same immune-response genes in the MS cohorts showed that the investigators were on the right track. When all the data were compiled and analysed, more than 50 separate genome regions were identified as influencing MS susceptibility in specific ways.

This phase of the genetic studies produced some fascinating surprises and showed how vitamin D research brings together the heritable and environmental influences on MS risk. One of the newly identified gene regions implicated CYP27B1, one of two enzymes required for the production of active vitamin D. Additional exome sequencing studies (which determine every nucleotide in the gene's protein-coding region) convincingly showed that reduced vitamin D levels were guilty of increasing MS susceptibility. Unexpectedly, some MS patients were found to carry single copies of rare variants of CYP27B1 that were defective enough to lead to rickets if two copies were present.

In summary, the evidence strongly indicates that low levels of vitamin D can predispose someone to MS. The lack of vitamin D could be due to insufficient sunlight or dietary intake, or to a genetic inability to convert vitamin D precursors to the vitamin itself. Additional research has even shown that some of the previously identified MS-susceptibility genes can be regulated in part by vitamin D.

These findings open the floodgates to a torrent of practical questions, many of which are under investigation in clinical studies. Can MS be prevented by raising vitamin D levels in high-risk groups such as the children of MS patients? Can patients with MS benefit by raising their levels of vitamin D after diagnosis? Do vitamin D levels play any part in the variable response to MS treatments? Finally the frustratingly vague statement that “MS is caused by genetic and environmental factors” is giving way to testable hypotheses about how to turn knowledge into better outcomes for patients — and vitamin D is at the centre of this process.