VDR Polymorphisms – What do they do, and how?

Which mutations are we talking about?

VDR Taq rs731236
VDR Bsm rs1544410

These are the two vitamin D receptor polymorphisms which Genetic Genie will report on if you upload your DNA analysis from 23andme to them.

There are other Vitamin D receptors and other polymorphisms.

Nutrahacker does not report on any Vitamin D receptor polymorphisms.

Need more vitamin D… Need more vitamin D….

Definition

These are variations in the vitamin D receptor, also known as the calcitriol receptor. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene. These polymorphisms are quite common in the general population.

What does this do normally?

This receptor is a part of your body cells which reacts to calcitriol, which is the activated form of vitamin D properly known as 1,25-dihydroxy vitamin D. On blood tests it is usually called “1,25 OH D”.

[Some blood tests measure inactivated vitamin D, which is indicated by 25 OH D. The levels of these two forms of vitamin D vary independently of each other and your tested level of one is no indication of your level of the other form.]

Vitamin D is a steroid hormone and also a precursor to other hormones.

When activated, this VDR receptor works with the retinoid-X receptors (there are two) and produces substances that help calcium and phosphate absorption, bone formation, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have been linked to osteoarthritis, diabetes, cancer, cardiovascular disease, and tuberculosis.

The retinoid-X receptors are co-dependent with the VDR receptor and they are involved in the process of making thyroid hormones and steroid hormones (e.g. cortisol and testosterone and dopamine). Retonoid-X receptors rely on vitamin A.

What does this polymorphism cause?

As of April 2014, three adjacent restriction fragment length polymorphisms for Bsm, Apa, and Taq, respectively, at the 3′ end of the VDR gene have been the most frequently studied. The influence of VDR gene polymorphisms on VDR protein function and signalling is still largely unknown.

We just have a few pieces of information so far.

Bone disease

Mutations in this gene have been associated with a type of rickets (a disease that involves soft, distorted bones) which does not respond to treatment with vitamin D. Patients with this disease had a homozygous mutation (that means one mutated gene inherited from each parent) in one of the VDR receptor genes. In this case, the mutation is clearly a DOWNREGULATION of the gene.

Low dopamine

It is well known that glucocorticoids decrease (downregulate) expression of the vitamin D receptor. This means they make it become less active. If the vitamin D receptor is already less effective than normal, the effect may be severe.

Glucocorticoids include cortisol and aldosterone. Doctors who treat patients with autism, lyme disease and CFS have observed that patients with this VDR polymorphism have very low levels of the steroid hormones cortisol, aldosterone, testosterone and other corticosteroids and dopamine. Vitamin D is a steroid itself, that is the precursor to these other steroids.

Dopamine is a calming neurotransmitter. The words dopey and dopamine are derived from the same etymological source – dopamine makes you feel sleepy, calm, relaxed and not very attentive. It also improves your ability to tolerate pain.

Cortisol is the “stress hormone” which hypes you up for fight or flight situations.

Since an increase in cortisol will further lower expression of the vitamin D receptor, the equilibrium between these hormones can be seriously disturbed. An activity that stimulates cortisol production can further impair dopamine production and lead to a runaway dominance of cortisol. In this situation the heart may pound, blood pressure may be raised and some people are unable to sleep for days at a time. This sensation is often described as “tired but wired”.

Some other methylation cycle mutations (COMT) impair the ability of the body to break down dopamine. People with both COMT and VDR mutations have an impaired ability to make dopamine and an impaired ability to get rid of it. It would be great if these two mutations just cancelled each other out, but instead they result in extreme volatility as the body just cannot keep dopamine at the right level.

This will result in moodiness, and mood swings. When dopamine is low you will feel all your aches and pains more intensely and have difficulty relaxing even when you are tired. You may find it hard to switch off and find your head is full of thought about what you hve done that day, or have to do, so you cannot clear your mind and go to sleep.

Autistic children with low dopamine are more likely to have temper outbursts, get fixed in a mood of anger or agitation (often about something totally unimportant) and end up in total meltdowns. They will typically do all the kind of things that make irritating people tell you your child really needs discipline.

Impaired immune fuction

People with a VDR mutation will be aware that their immune system does not work as well as other people’s. Vitamin D regulates the balance between the Th1 and the Th2 immune function.

There is one theory that they will be more likely to develop autoimmune diseases but this has not been verified. To lower risk of autoimmunity, the four “Foods of the Devil” for autoimmunity should be avoided: gluten, soya, dairy and egg.

Low vitamin D

People with VDR polymorphisms often have low levels of vitamin D as well, though in many cases they have low inactivated vitamin D and normal activated vitamin D. The reason for this is not known.

These people often report that they do not see a rise in serum levels of vitamin D even when they take very large dose supplements.

In recent studies, several associations between low levels of vitamin D, or hypovitaminosis D, and neuropsychiatric disorders have begun to surface. These disorders include, but are not limited to: Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, and schizophrenia. However, an actual mechanism of attack for each of the conditions has yet to be solidified. Many researchers have questioned whether the depletion of vitamin D actually causes these disorders or if vitamin D is a symptom of these disorders. Future research is needed to fully answer these questions.

Treatment

Since the downstream targets of the VDR are various hormones and other targets, there does not seem to be a simple way to bypass this problem.

James Roberts of the Heartfixer Clinic suggests some ways of dealing with the symptoms that arise from the lack of dopamine:

“Dopamine precursors such as quercetin, ginkgo biloba, and the herb macuna puriens might be helpful, as would a diet high in tyrosine, the amino acid precursor to dopamine.  Other methyl donors, including melatonin, TMG, turmeric, theanine, along with MSM and SAMe (the latter two only for CBS (-/-) individuals) would make sense. To support BHMT, instead of Phosphatidylserine, we would use… Phosphatidylserine and DMAE, a methyl donor.  Rather than using GABA to deal with excitotoxicity, we would use… GABA with the methyl donor threanine.”

Some people also find it helpful to take the old-fashioned soporific antihistamine tablets. These will not tackle to problem head-on but they may be enough to give you the quick fix of a decent night’s sleep and an outlet from the “tired but wired” sensation.

Useful links and sources

VDR mutations

http://www.sciencedirect.com/science/article/pii/S0378111904003075

Vitamin D and neurology

http://en.wikipedia.org/wiki/Vitamin_D_and_neurology

Online encyclopaedia of the human genome. You can look up rs and SNP codes to find links to online research articles relating to that gene. Their database is growing constantly.

http://www.snpedia.com/index.php/SNPedia

Symptoms and possible causes of vitamin D deficiency

http://en.wikipedia.org/wiki/Hypovitaminosis_D

James Roberts treatment suggestions. Dr. Roberts is a cardiologist who specialises in the prevention of cardiovascular disease by reducing homocysteine, a harmful by-product of methylation which builds up in people with methylation problems and has been proven to cause cardiovascular disease.

http://www.heartfixer.com/AMRI-Nutrigenomics.htm#VDR Taq:  Vitamin D Receptor Taq Abnormality

Please note, I am not a doctor and this is not medical advice. I am a patient with this mutation and this is all based on internet research.