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Genetic study shows direct link between vitamin D and MS susceptibility ’gene’


Researchers have found evidence that a direct interaction between vitamin D and a common genetic variant alters the risk of developing multiple sclerosis (MS).

The research, published on 6 February in the open-access journal PLoS Genetics, suggests that vitamin D deficiency during pregnancy and the early years may increase the risk of the offspring developing MS later in life.

MS is the most common disabling neurological condition affecting young adults. More than 85 000 people in the UK and 2.5 million worldwide are thought to suffer from the condition. It results from the loss of nerve fibres and their protective myelin sheath in the brain and spinal cord, causing neurological damage.

The causes of MS are unclear, but it has become evident that both environmental and genetic factors play a role. Earlier studies showed that populations from Northern Europe have an increased risk of MS if they live in areas receiving less sunshine. This supports a direct link between deficiency in vitamin D, which is produced in the body through the action of sunlight, and increased risk of developing the disease.

The largest genetic effect by far comes from the region on chromosome six containing the gene variant known as DRB1*1501 and from adjacent DNA sequences. While one in 1000 people in the UK are likely to develop MS, this number rises to around one in 300 among those carrying a single copy of the variant and one in 100 of those carrying two copies.

Now, in a study funded by the UK’s MS Society, the MS Society of Canada, the Wellcome Trust and the Medical Research Council, researchers at the University of Oxford and the University of British Columbia have established a direct relationship between DRB1*1501 and vitamin D.

The researchers found that proteins activated by vitamin D in the body bind to a particular DNA sequence lying next to the DRB1*1501 variant, in effect switching on the gene.

“In people with the DRB1 variant associated with MS, it seems that vitamin D may play a critical role,” says co-author Dr Julian Knight, a Wellcome Trust Senior Research Fellow. “If too little of the vitamin is available, the gene may not function properly"

“We have known for a long time that genes and environment determine MS risk,” says Professor George Ebers, University of Oxford. “Here we show that the main environmental risk candidate – vitamin D – and the main gene region are directly linked and interact.”

Professor Ebers and his colleagues believe that vitamin D deficiency in mothers or even in a previous generation may lead to the DRB1*1501 gene functioning differently in offspring.

The finding – that the environment interacts directly with the background genetics of MS – is a first for a common autoimmune condition and complements research recently published in Human Molecular Genetics by Professor Ebers’s group. In this, they showed that environmental effects on the same gene region can increase the risk of developing MS even further and can be inherited.

These so-called ‘epigenetic effects’ are being seen as increasingly important by scientists and there may be ways in which the effects reported in these two papers are related.

“Epigenetics will have important implications, not only for MS, but for other common diseases,” says Professor Ebers. “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.”

The authors hypothesise that this gene-environment interaction may affect the ability of the thymus, a key component of the immune system, to perform its regular tasks. The thymus produces an army of T cells, which identify invading pathogens, such as bacteria and viruses, and attack and destroy them. There are millions of different T cells, each designed to recognise a specific pathogen, but there is a risk that one type might mistakenly identify one of the body’s own cells or proteins.

Ordinarily, the thymus will regulate the T cells and delete those that pose the greatest risk of attacking the body’s own cells and proteins. However, the researchers believe that in people who carry the DRB1 variant associated with MS, a lack of vitamin D during early life might impair the ability of the thymus to delete these T cells. These then go on to attack the body, leading to a loss of myelin on the nerve fibres.

“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,” says lead author Dr Sreeram Ramagopalan. “Vitamin D is a safe and relatively cheap supplement with substantial potential health benefits. There is accumulating evidence that it can reduce the risk of developing cancer and offer protection from other autoimmune diseases.”

The research has been welcomed by Simon Gillespie, Chief Executive of the MS Society (UK).

“These remarkable results tie together leading theories about the environment, genes and MS, but they are only part of the jigsaw,” says Mr Gillespie. “This discovery opens up new avenues of MS research and future experiments will help put the pieces together.”

Notes for editors

1. Ramagopalan S et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genetics, 6 Feb 2009. A preview copy of the paper is available [PDF 420KB].

2. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending more than £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.

3. The MS Society is the UK’s largest charity dedicated to supporting everyone living with or affected by MS, providing respite care, an award-winning freephone helpline (0808 800 8000), specialist MS nurses and funds around 80 vital MS research projects in the UK.

4. The Wellcome Trust Centre for Human Genetics was established to undertake research into the genetic basis of common diseases. The scientific objective of the Centre is to explore all aspects of the genetic susceptibility of disease. The Centre houses multi-disciplinary research teams in human genetics, functional genomics, bioinformatics, statistical genetics and structural biology.

5. The Medical Research Council supports the best scientific research to improve human health. Its work ranges from molecular level science to public health medicine and has led to pioneering discoveries in our understanding of the human body and the diseases which affect us all.

6. The University of Oxford’s Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of the University of Oxford’s income and expenditure and two-thirds of its external research income.

Oxford’s world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia.

Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for tuberculosis, malaria and HIV, which are in clinical trials.


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