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A ChIP-seq-defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution

  • MS Society Funded

Summary

The extent to which vitamin D deficiency may increase susceptibility to a wide range of diseases is dramatically highlighted in research just published. Scientists have mapped the points at which vitamin D interacts with DNA – and identified over two hundred genes that it directly influences. Sreeram V. Ramagopalan, Andreas Heger, Antonio J. Berlanga, Narelle J. Maugeri, Matthew R. Lincoln,1 Amy Burrell, Lahiru Handunnetthi, Adam E. Handel, Giulio Disanto, Sarah-Michelle Orton Corey T. Watson, Julia M. Morahan, Gavin Giovannoni, Chris P. Ponting, George C. Ebers, and Julian C. Knight. Genome Research August 23, 2010.

Details
It is estimated that one billion people worldwide do not have sufficient vitamin D. This deficiency is thought to be largely due to insufficient exposure to the sun and in some cases to poor diet. As well as being a well-known risk factor for rickets, there is a growing body of evidence that vitamin D deficiency also increases an individual's susceptibility to autoimmune conditions such as multiple sclerosis (MS), rheumatoid arthritis and type 1 diabetes, as well as certain cancers and even dementia.

Now, in a study whose funders include the Medical Research Council, the MS Society, the Wellcome Trust, the MS Society of Canada and the MS Scientific Research Foundation, researchers at the University of Oxford have shown the extent to which vitamin D interacts with our DNA. DNA sequencing technology was used to create a map of vitamin D receptor binding across the genome. The vitamin D receptor is a protein activated by vitamin D, which attaches itself to DNA and thus influences what proteins are made from our genetic code.

The researchers found 2,776 binding sites for the vitamin D receptor along the length of the genome. These were unusually concentrated near a number of genes associated with susceptibility to autoimmune conditions such as MS, Crohn’s disease, systemic lupus erythematosus (or 'lupus') and rheumatoid arthritis, and to cancers such as chronic lymphocytic leukaemia and colorectal cancer.

They also showed that vitamin D had a significant effect on the activity of 229 genes including IRF8, previously associated with MS, and PTPN2,associated with Crohn’s disease and type 1 diabetes.

The main source of vitamin D in the body comes from exposing the skin to sunlight, although a diet of oily fish can provide some of the vitamin. Research has previously suggested that lighter skin colour and hair colour evolved in populations moving to parts of the globe with less sun to optimise production of vitamin D in the body. A lack of vitamin D can affect bone development, leading to rickets; in pregnant mothers, poor bone health can be fatal to both mother and child at birth, hence there are selective pressures in favour of people who are able to produce adequate vitamin D.

This new study supports this hypothesis, having found a significant number of vitamin D receptor binding sites in regions of the genome with genetic changes more commonly found in people of European and Asian descent. It is probable that skin lightening as we migrated out of Africa resulted from the necessity to be able to make more vitamin D and prevent rickets: vitamin D deficiency led to pelvic contraction resulting in increased risk of fatality of both mother and unborn child, effectively ending maternal lineages unable to find ways of increasing availability of the vitamin.

National Research and Programs with permission of the Wellcome Trust