Thursday February 5 2009
MS impairs the ability of nerve cells to transmit signals around the body
“Multiple sclerosis could be prevented through daily vitamin D supplements” reports The Times, stating that scientists have found the first causal link between the “sunshine vitamin” and a gene that increases the risk of the incurable neurological condition, known as MS.
The news comes from research into how vitamin D interacts with the genes that make certain people more likely to develop MS. The researchers claim their study strongly implies that vitamin D deficiency increases the risk of developing MS among susceptible individuals. This study was not attempting to find a cure or treatment for MS.
The Times reports that spending more time in the sun (which makes the body produce vitamin D) might protect against the condition. However, exposure to high levels of sunlight can damage the skin and cause cancer. The newspaper also suggests the use of vitamin supplements by pregnant women might reduce their children’s risk of the condition. Current advice for pregnant women is that they can choose to take up to 10 micrograms of vitamin D a day and to contact their GP for specific advice.
Although preliminary, this important study does point the way to future research into the actions of vitamin D and particularly the complex interactions between sunlight, vitamin D and genes.
Where did the story come from?
This study was conducted by Prof. George Ebers, Dr Julian Knight and colleagues from Oxford University, John Radcliffe Hospital and various institutions in Canada. The study was funded by the Multiple Sclerosis Society of Canada, the Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom. It was published online in the peer reviewed journal PLoS genetics.
What kind of scientific study was this?
This genetic and laboratory study looked at whether there might be a relationship between vitamin D and genetic susceptibility for MS. The authors explain that MS is an inflammatory disease of the nervous system.
One particular area in the genome (genetic make up) on chromosome 6, called the Major Histocompatibility Complex (MHC), is reported to have the greatest genetic influence on a person’s risk of MS. Within this MHC one particular section called the HLA-DRB1 locus is known to influence MS risk. Having one particular variation of this locus, called the HLA-DRB1*15 haplotype, increases the risk of MS three fold.
There is also evidence to suggest that environmental factors act at a population level to influence the geographical distribution of MS. This is unusual, and even in populations of the same ethnicity the risk can vary by up to three times depending on geographic location. There is also a trend for a higher incidence of the disease in areas with less sunshine, such as Scotland and Northern European countries.
This has led to the suggestion that sunshine and particularly vitamin D, which is synthesised in the body in response to sunlight, may be connected to the environmental causes of MS. This study aimed to look at whether vitamin D might directly affect the function of specific genes within the MHC.
Once in the body vitamin D can switch certain genes on. To do this it needs to bind to a protein called the vitamin D receptor (VDR), which in turn binds to a particular sequence of the letters in the DNA called vitamin D response elements (VDREs).
To investigate this, the researchers used a computer program to look at genes within the MHC for VDREs in DNA from a person with the HLA-DRB1*15 haplotype on both of their copies of chromosome 6. They looked at the HLA-DRB1, -DQA1 and -DQB-1 genes, and at the DNA around them, as well as the IL2RA and IL7RA genes.
The computer program identified a piece of DNA that looked like a VDRE. The researchers then carried out a case-control study in 322 people to see if its sequence varied in people with MS (cases) and people without MS (controls). These people were all homozygous for (had two copies of) the HLA-DRB1*15 haplotype. The researchers also looked at the DNA from 168 people who did not carry this high-risk haplotype, but were homozygous for other haplotypes, which were not associated with increased risk of MS, or conferred only a modest increase in risk.
To further test whether vitamin D could bind to the VDRE-like sequence, the researchers carried out experiments where they mixed the VDR with a piece of DNA containing the VDRE-like sequence. This was to see if there was evidence that the two were specifically binding to each other. Cells were then grown in the laboratory that were homozygous for the HLA-DRB1*15 haplotype. Half of the cells were treated with vitamin D for 24 hours, and the other half had no vitamin D. The researchers then used specific techniques to see if the VDRE was bound to the VDRs.
They then investigated if the VDRE could affect how genes are switched on in living cells. They took a piece of DNA containing the VDRE and attached it to a gene that produces a protein that can cause a light-producing reaction under certain conditions (called a reporter gene because of the ability to tell if it is switched on or off). This piece of DNA was then inserted into cells in the laboratory to see whether exposing the cells to vitamin D caused the reporter gene to be switched on. The researchers repeated this experiment using the variant forms of the VDRE found in the no- or moderate-MS-risk haplotypes.
Finally, the researchers investigated whether having the VDRE could affect the switching on of the HLA-DRB1 gene. They did this by comparing the level of HLA-DRB1 protein on the surface of cells that carried two copies of the HLA-DRB1*15 and cells that carried two copies of the less active VDRE variant haplotypes. They also looked at how treating these cells with vitamin D affected levels of HLA-DRB1.
What were the results of the study?
The researchers identified a possible site for vitamin D binding (a possible VDRE) in the region that controls the switching on of the HLA-DRB1 gene (called its promoter region). They found no variations in this possible VDRE sequence in people who had two copies of the high risk HLA-DRB1*15 haplotype, regardless of whether they had MS or not.
However, people who had two copies of the haplotypes that were not associated with MS, or conferred only a modest risk of MS, did have variations within the possible VDRE that might affect vitamin D binding. Tests in the laboratory showed that the VDR protein could bind to the potential VDRE when mixed together, and that the two would bind to each other in cells grown in the laboratory.
They also found that the VDRE could lead to switching on of reporter genes in the presence of vitamin D in cells in the laboratory, but that the variants of VDRE found in the lower risk MS haplotypes did not. Cells that had two copies of the HLA-DRB1*15 haplotype, and therefore the working VDRE, had higher levels of HLA-DRB1 protein than those that did not. Treating the cells that had two copies of the HLA-DRB1*15 haplotype with vitamin D increased the levels of this protein even more, but did not affect the other cells.
What interpretations did the researchers draw from these results?
The researchers say that their study provides further support for vitamin D as a strong environmental risk factor for MS. They say that their findings “imply direct interactions between HLA-DRB1, the main genetic susceptibility locus for MS, and vitamin D, a strong candidate for mediating the environmental effect”. They also say that as there is a high frequency of vitamin D insufficiency in the general population their data support the case for supplementation to reduce the number of people who have MS.
What does the NHS Knowledge Service make of this study?
This is important research and will be of major interest to people living with MS. However, this study concentrated on susceptibility to MS among populations, rather than looking for a cure or treatment to help those already living with the condition. “These are exciting advances, but unfortunately we have yet to find and solve the cause of MS… what I think we’ve done is add another piece to the jigsaw” said Dr Julian Knight, one of the authors.
Multiple genetic and environmental factors play a role in the development of MS, and this work advances scientific understanding of how these factors interact. This particular study focused on how vitamin D might interact with sections of the DNA of certain susceptible people.
Although The Times speculates that pregnant women might reduce their child’s risk of developing MS by taking vitamin D supplements, the authors state that the decision to use supplements “should still be between the patient and their physician”. Current NICE guidance states that pregnant or breastfeeding women may choose to take up to 10 micrograms of vitamin D a day and that women should speak to their GP for specific advice.
The newspaper also discusses the possibility of changing the recommended sun exposure limits. While sunlight does stimulate vitamin D production, the dangers of high levels of sun exposure are well documented, and sunbathing to increase vitamin D levels may be harmful. In addition, the study did not compare whether sunlight or supplements are a better source of vitamin D, but only looked at the chemical and biological interaction of vitamin D and genes in a laboratory.
This work will undoubtedly lead to further research into the risk factors behind MS, and potentially other serious conditions. Simon Gillespie, Chief Executive of the Multiple Sclerosis Society said that the research “is, of course, only part of the story, but what strikes me is opportunities and avenues for future research that it opens up.” At present trials are being conducted into whether vitamin D supplements can improve the symptoms of people living with MS.
The Multiple Sclerosis Society can give individuals further advice on this study through their website and helpline, on 0808 800 8000.