The Association Between Vitamin D and Multiple Sclerosis Risk: 1,25(OH)2D3 Induces Super-Enhancers Bound by VDR
Ming Lu, Bennet J. McComish, Kathryn P. Burdon, Bruce V. Taylor
and Heinrich Körner
Front Immunol. 2019 Mar 19;10:488. doi: 10.3389/fimmu.2019.00488.
1. The cause of MS is not known. What we do know is that certain genes increase the risks for developing MS. Over 200 such genes have been identified.
2. There also are environmental conditions that increase susceptibility to the disease. One of these is a low level of vitamin D.
3. The reason(s) that low levels of vitamin D increase risk for MS are not known. Vitamin D can affect immune responses in both good and bad ways.
4. Many studies looked at the effects of giving supplemental vitamin D to persons with MS. The results are mixed, with some studies showing benefit and others showing worsening of disease. There is a good review of the studies.
5. Most benefits to supplemental vitamin D were noted in persons with low vitamin D levels to start with. Little benefit was noted to taking extra vitamin D in persons who already had normal to high levels of this vitamin.
6. The paper by Lu et al discusses another potential mechanism for how Vitamin D could affect susceptibility to MS.
7. Vitamin D binds to chemicals in the blood that result in changes to a cell’s DNA. The changes result in openings in the dense material of DNA called “chromatin”. Opening of the chromatin allows certain genes in the DNA to be both “exposed” and “activated.” When a gene is activated it can result in new proteins being made.
8. Chemicals that “activate” genes, and induce the production of proteins are called ”promoters,” “enhancers,” and “transcribers.”
9. Vitamin D binds to a vitamin D receptor (VDR) that in turn binds to a powerful group of enhancers called “super enhancers”. Female hormones called estrogens also can induce super-enhancers.
10.Regions of DNA containing super-enhancers can be identified and genes in that vicinity may have a greater chance of being activated. Thus if a cancer gene is located near a region of super-enhancers, there is a greater risk of developing cancer.
11. Lu and colleagues studied the locations of estrogen-induced super-enhancers in persons with MS and looked if these super-enhancers were near genes known to increase the risk of developing MS. In specific they looked at susceptibility genes also affected by vitamin D. The gene sequences they studied came from human immune cells called monocytes.
12.Their results indicated that higher than expected numbers of vitamin D stimulated risk genes were in regions near super-enhancers.
13.There are at least two possibilities for how super-enhancers could affect vitamin D responsive risk gene. One is that the super-enhancers regulate other genes in the vicinity of the risk genes that in turn prevent activation of risk genes. In such instances, supplemental vitamin D would be beneficial.
14.The other possibility is that estrogen-induced, super-enhancers increase the risk vitamin D responsive gene activation. In that situation, adding extra vitamin D would not be beneficial.
15.The bottom line is that vitamin D can have direct effects on genes known to increase the risk of developing MS, and these effects may vary. In individuals with low vitamin D levels, risk-gene activation may be increased with supplemental vitamin D being of benefit. With high or normal levels of vitamin D risk gene activation may be increased and supplemental vitamin D may not benefit.
16.Since genes inherited from one’s parents will vary greatly, supplemental vitamin D may not be of benefit to all persons with MS, and will vary with the particular genes inherited. This could explain the varying results seen in studies of vitamin D supplementation in persons with MS.
Many MS-specialty physicians prescribe supplemental vitamin D for their MS patients. The main reasons are that taking extra vitamin D is usually very safe and may have a beneficial effect on the clinical course of the disease. However, data consistently establishing benefit from low or high dose vitamin D supplements is lacking. Indeed, some studies, summarized in a recent review that high dose supplements could, in some individuals, actually change immune responses for the worse and possibly increase disease activity. Since low levels are vitamin D are an established risk factor for developing MS, why wouldn’t vitamin D supplementation by universally beneficial? The paper by Lu et all provides a possible answer. Vitamin D binds to a vitamin D receptor (VDR) that in turn leads to the generation of products that increase gene activity (super-enhancers). Vitamin D also acts on genes more directly, so-called “vitamin D responsive genes.” Lu and colleagues show that super-enhancers induced by female hormones, or estrogens, are located to a much greater extent than expected next to genes associated with an increased risk for developing MS. There are over 200 genes implicated as risk-increasing genes, and the numbers and types of such genes will vary from individual to individual. Thus, it is possible that low levels of vitamin D in some individuals allow increased activation of risk-increasing genes, while higher levels of vitamin D in other individuals may either not effect risk-increasing genes or result in activation of other genes that reduce suppression of risk-increasing genes.
How do these observations affect clinical practice? If a person’s vitamin D levels are low, prescribing Vitamin D supplementation would be reasonable. However, if baseline vitamin D levels are normal or high, adding vitamin D to a person with MS’s drug regimen may not be useful, and possibly even harmful. Discussion of these issues with a person’s neurologist should be considered.
An abstract of the article is available.