Variations in the Vitamin D Receptor (VDR) may increase your need for Vitamin D3 from sun exposure, food, and supplements.
Vitamin D function is much more than bone and calcium metabolism, it has importance in immune regulation and has been linked to lower risk of cancers and allergic diseases.
Intake of Vitamin D has wide-reaching effects on most body tissue types and may help reduce system-wide inflammation, and promote healthy gut health and immune tolerance (1).
Low levels of vitamin D have been implicated in food allergies, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, autoimmune thyroid diseases, and autoimmune gastritis (1; 2).
Vitamin D status sounds like something we should pay attention to, right?
Normal Vitamin D Formation and Activation in the Body
Vitamin D is formed from a reaction triggered by UV light on the skin, and converted to 25-hydroxy vitamin D (calcidiol) in the liver where it is stored. When you have your Vitamin D measured by your doctor, typically it is the D3/25 Hydroxyvitamin D/Calcidiol form.
Vitamin D can also be consumed as a supplement, as well as in dietary sources. Ergocalciferol (Vitamin D2) can be taken as well, but it is considered less ideal as it is not as well absorbed. Both vitamins D3 and D2 can be converted to “active” vitamin D known as 1,25 dihydroxyvitamin D or Calcitriol in the kidneys.
Calcitriol is carried around the blood by the vitamin D binding protein. Eventually, calcitriol finds it way to the cell where it can bind to the Vitamin D Receptor (VDR).
The VDR is located in the nucleus of the target cell where all the fun genetic things happen. When acted on by calcitriol, the VDR will regulate both the innate and adaptive immune systems – affecting the action of monocytes, dendritic cells, T and B cells.
The VDR has been found on just about every tissue type in the human body – including immune cells. Vitamin D is also known to have non-VDR related functions by binding to a separate receptor called the MARRS (membrane-associated rapid response steroid-binding) receptor.
As vitamin D is capable of both gene and non-gene actions, it shows how intricately it can be woven into a very wide range of roles in the body (3).
Normal Role of the Vitamin D Receptor
Once activated by calcitriol, VDR can block the maturation of dendritic cells (therefore promoting immature and “tolerant” dendritic cells). As such, VDR promotes T cell tolerance, while also bringing balance to the adaptive immune response.
Vitamin D intake also promotes the production of regulatory T-cells (Tregs) – which suppress various immune cells and further help to promote a balanced immune response (2).The binding of calcitriol to VDR ultimately turns down production of Th1 immune factors including IL1, IL2, IL6, and IL12, and interferon gamma, and tumor necrosis factors alpha and beta. There are mixed studies on the effect of VDR activation on Th2 cells, but the general bias is toward Th2 cell promotion which is helpful as many autoimmune processes are Th1-dominant.
VDR activity is generally accepted to promote both Th1 and Th2 balance. It also inhibits the production of aggressive Th17 cells which are involved in direct autoimmune damage to tissues (4).
What happens if the VDR is faulty?
VDR Polymorphisms (VDR Fok1, Bsm1, Taq1, Apa1) and Disease Risk
Sometimes, a healthy storage of vitamin D may not be enough.
There are a number of genetic polymorphisms or “versions” of the VDR gene that can alter its classical function. Slight differences in the version of the VDR gene may alter risk to inflammatory and immune-related disease. The most common VDR polymorphisms include FokI, BsmI, TaqI, and ApaI.
Polymorphisms are not the only factor to consider when looking at VDR activity. Higher levels of pathogens in the microbiome (5) and certain specific infections such as Epstein-Barr Virus, HIV or Lyme Disease may also block the binding of calcitriol to VDR – causing global disruptions in the regulation of immunity and inflammation (6) while also increasing your need for Vitamin D.
A VDR polymorphism may also increase susceptibility to infection in the first place through alterations in immune balance. For instance, it has been reported that the VDR FokI polymorphism may increase susceptibility to Respiratory Syncitial Virus (RSV)-bronchitis (7).
The VDR Fokl polymorphism is associated with lower levels of T-helper cells -despite the VDR being acted on by Vitamin D. Those carrying the VDR FokI polymorphism may have reduced number of T helper cells, as as such – may be at higher risk of imbalanced T-cell immunity (8).
A meta-analysis of VDR polymorphisms and cancer risk found the VDR Fok1 polymorphism to be associated with an increased risk for breast and ovarian cancer, while the VDR BsmI version was associated with protected risk (9). The VDR BsmI version may also be protective against melanoma (10).
The BsmI polymorphism is not without its risk profile either. The VDR TaqI and BsmI polymorphisms have also been associated with increased risk of asthma (11). Significant associations have also been reported for FokI, BsmI and TaqI with prostate cancer risk, FokI, BsmI, ApaI with breast cancer, FokI, BsmI, TaqI for colon and rectal cancer risk, and FokI, BsmI, and TaqI and skin cancer, respectively (12). VDR polymorphisms have also been associated with systemic autoimmune disorders such as multiple sclerosis (4)
Generally, vitamin D levels are recognized to be inversely correlated with many types of cancer, as well with cancer survival rates especially for breast cancer, lymphoma and colorectal cancer. Every 10 nmol/L increase in vitamin D3 has been linked to a 4% increase in cancer survival (13).
I Carry VDR Polymorphisms, Now What?
There a number of services available that allow you to assess which VDR Polymorphisms you carry, if any. I choose 23andMe.com. For $99, you can have access to your raw genetic data – which can then be ran through 3rd party platforms that can help you organize the date.
High doses of Vitamin D3 therapy may be able to stimulate the VDR and support normal levels of activity, even if you have VDR polymorphisms (14).
Due to variations in the VDR gene, however, a “U-shaped” curve of disease risk may best describe the influence of VDR polymorphisms.
A “U-shaped” distribution simply means that having both too high or too low levels of Vitamin D may increase your risk of disease when you carry a VDR polymorphism. The split as to who is at high risk or low risk depending on a high or low status of vitamin D3 may depend on VDR genotype (15).
As the science of nutrigenomics is so young, most of the details still need to be determined.
Chris Kresser, LAc mentions that while the optimum level of D3 may be at least 35 ng/mL for most people, the vitamin D needs of those with VDR polymorphisms may be as high as 60-70 ng/mL.
When getting Vitamin D levels to this higher range of normal, Kresser keeps track of serum calcium for signs of vitamin D toxicity. Vitamin D toxicity may increase risk for kidney stones, fractures, heart problems, and certain cancers.
Many holistic professionals recommend a vitamin D level between 40-80ng/mL. Kresser reflects on Chris Masterjohn, PhD‘s assertion that the problems with high vitamin D levels, may have more to do with a deficiency in both vitamins K2 and vitamin A than it does a surplus of Vitamin D.
Without adequate K2 and A, patients may actually start to lose bone density when their vitamin D levels surpass 45 ng/mL. Masterjohn asserts that Vitamin A and vitamin D may share activity in the body – particularly when it comes to bone health.
In other words, you may realize additional benefits of vitamin D beyond the 45 ng/mL, but only in the presence of adequate levels of vitamins A and K2.
Otherwise, Kresser and Masterjohn seem to agree that excess Vitamin D may increase health risks.
If vitamin A and K2 levels are adequate, you may realize additional Vitamin D benefits up until you reach 80ng/mL. After you surpass 80ng/mL, that’s when the risk profile may shift again from positive to negative reflecting that “U-shape” distribution of risks and benefit.