Vitamin D's effect on MS risk may relate to gene expression

Vitamin D deficiency has been associated with increased risk of MS in several studies. However, the basis for this relationship remains unknown. A study published last year provided evidence that vitamin D affects the expression of the leading MS susceptibility gene (HLA DRB1*1501), indicating that gene expression effects may at least partially account for vitamin D's connection with MS. Now a new study appearing in the journal Genome Research further explores the connection between vitamin D, gene expression, and MS (as well as other diseases). Click here for the abstract and here for the full-text PDF.

Gene expression is the process by which a DNA sequence is copied into messenger RNA, which is then decoded by cellular structures to manufacture a protein needed by the cell. Whether and when a particular gene is expressed can be affected by different factors. Some of these factors are molecules that bind to DNA to increase or decrease copying of a gene sequence into mRNA. One of these factors, called Vitamin D receptor (VDR), becomes activated after it binds to a form of vitamin D called calcitriol. Once activated, VDR can then latch on to certain sequences on the chromosome which affects (increases or decreases) the expression of nearby genes. Therefore, being deficient in vitamin D can directly affect the level of production for certain proteins in a person's cells.

In this new study, a team of researchers used cell lines from two people to find 623 places in the genome where VDR binds. These locations are called vitamin D response elements, or VDREs. They found many more VDREs (2776) after exposing the cells to calcitriol. They also measured gene expression within these cells before and after exposure to calcitriol, and found 226 genes for which gene expression was increased and 3 for which it was decreased. Many of these genes play a role in immune function, and about a quarter of these genes had a VDRE nearby.

Next, the team analyzed the locations of the VDREs they had detected to see if they were located near to disease susceptibility genes (genes for which certain variants are more frequently found in people with a condition -- like HLA DRB1*1501 and MS). They found that many VDREs were located near genes that had been previously associated with MS and other autoimmune diseases as well as certain cancers. For example, one of the new VDREs was found in the IRF8 gene, which has been associated with MS -- and IRF8 was also one of the genes for which calcitriol enhanced gene expression. They did not find that the actual variants associated with these diseases had the potential to directly disrupt VDRE function, which would have helped solidify this line of investigation. However, perhaps they are inherited along with other nearby genetic variants that do affect VDR binding.

Finally, the researchers analyzed data from another study that had measured gene expression in people with MS and control subjects. They compared the list of genes that were expressed to a greater or lesser degree in MS subjects with their list of genes that had nearby VDREs. They found that VDR binding was indeed enriched in those genes that were differentially expressed in the MS subjects.

This study moves us a little farther along in understanding why vitamin D deficiency has been linked with MS. If vitamin D does play an active role in the disease -- by affecting expression of several genes -- then it may be helpful to correct any deficiency even after MS has been established since these genes may also influence the course of MS. In fact, another recent paper has found that vitamin D levels were connected with subsequent risk of relapse in people with MS. It would be interesting to extend this type of study to also include gene expression analysis. In the meantime, if you have MS and haven't yet discussed vitamin D with your doctor, perhaps that would be a good topic to bring up.