Researchers in the UK and Canada have discovered that vitamin D and a particular gene variant interact to increase the risk of developing multiple sclerosis (MS), and suggested that vitamin D deficiency during fetal growth and early childhood may increase the risk of developing MS in later life.

The research was done by scientists at Oxford University in the UK and the University of British Columbia in Canada and is published as an open access article in the 6 February issue of the Public Library of Science. The research was funded by the UK’s MS Society, the MS Society of Canada, the Wellcome Trust and the Medical Research Council.

MS is the most common neurological condition that disables young adults. There are over 85,000 people in the UK living with MS, the worldwide figure is estimated at 2.5 million.

MS develops when the nerve fibres that send messages up and down the spine, in the brain and throughout the body degrade and lose their protective myelin sheath, rather like the insulation around electrical cables disintegrating and causing the wires to short circuit. The disease progresses gradually, intermittently at first, but with increasing irreversible neurological damage in later phases.

It is not clear what triggers MS, but more and more research points to two factors: environment and genes. Some studies have also shown that people who live in countries that have less sunshine, such as Northern Europe, are more prone to MS. Vitamin D is made in the body when it is exposed to sufficient sunlight, a fact that has led many researchers to investigate links between this and MS.

Scientists already knew that a region on chromosome 6, that contains the gene variant called DRB1*1501, and also DNA in neighbouring parts of the genome played a role in the development of MS. In the UK, the overall incidence of MS in the population is around 1 in every 1,000, but this becomes 1 in every 300 for those who carry one copy (ie they inherited it from one of their biological parents) of the gene, and 1 in every 100 for those people who inherit two copies.

Now with this new study, the researchers established a direct link between DRB1*1501 and vitamin D. They discovered that proteins activated by vitamin D bind to a particular DNA sequence next to the DRB1*1501 gene variant and that by doing this they switch the gene on.

Co-author Dr Julian Knight, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, said:

“In people with the DRB1 variant associated with MS, it seems that vitamin D may play a critical role.”

“If too little of the vitamin is available, the gene may not function properly,” he added.

As co-author Professor George Ebers, also from Oxford’s Wellcome Trust Centre for Human Genetics and the University’s John Radcliffe Hospital Department of Clinical Neurology, explained:

“We have known for a long time that genes and environment determine MS risk.”

“Here we show that the main environmental risk candidate — vitamin D — and the main gene region are directly linked and interact.”

Ebers and colleagues went so far as to say it was likely that vitamin D deficiency in mothers or even in a previous generation could affect the expression of DRB1*1501 in their children.

Ebers’s group has already published related research in the journal Human Molecular Genetics, where they showed that environment changes to the same region of the genome heightened the risk of developing MS and can be inherited. These are called “epigenetic” effects, and more and more studies are coming forward with this kind of evidence.

Ebers said that epigenetics will have important implications for other diseases too, not just MS.

“For mothers, taking care of their health during their reproductive years may have beneficial effects on the health of their future children or even grandchildren,” he said.

Speculating on their findings, the authors said perhaps the thymus, an important part of the immune system, is affected by the gene-environment interaction. The thymus makes millions of different kinds of T-cells that seek and destroy different types of invading pathogens like bacteria and viruses. If due to incorrect “programming” a type of T-cell fails to identify a pathogen correctly and attacks the body’s own cells or proteins instead, this is an autoimmune disease, of which MS is one kind.

Usually the thymus will control T-cell production and destroy any that are likely to behave in this way, but, the researchers suggest that the combination of the gene variant they have identified, and lack of vitamin D in early life, causes the thymus to malfunction and fail to delete the “faulty” T-cells, which in this case are incorrectly programmed to attack the nerve fibres and their myelin sheath and cause MS.

Lead author, Dr Sreeram Ramagopalan, who also works at the Wellcome Trust Centre for Human Genetics and the John Radcliffe Hospital in Oxford, said:

“Our study implies that taking vitamin D supplements during pregnancy and the early years may reduce the risk of a child developing MS in later life. Vitamin D is a safe and relatively cheap supplement with substantial potential health benefits.”

Ramagopalan also said there is growing evidence that vitamin D also reduces risk of cancer and other autoimmune diseases.

Simon Gillespie, Chief Executive of the MS Society (UK), welcomed the study, and said that the results brought together leading theories about the interplay between genes and environment. But they were only part of the jigsaw for MS:

“This discovery opens up new avenues of MS research and future experiments will help put the pieces together,” he added.

“Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D.”
Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton S-M, et al.
PLoS Genetics 2009, 5(2): e1000369.
Published online February 6, 2009.

Click here for open access article.

Sources: Public Library of Science.

Written by: Catharine Paddock, PhD