Vitamin D, MTHFR, and the VDR Gene SNPs

Like everything else we talk about, MTHFR and vitamin D have a curious relationship. Vitamin D doesn’t link into the folate cycle, the methylation cycle, or the BH4 pathway so it isn’t an obvious connection, but it’s thought to be linked through the sharply named “Folate-Vitamin D-UV Hypothesis of Skin Pigmentation.” So let’s break this down along with a couple of gene SNPs that affect vitamin D specifically.

Vitamin D

Vitamin D is a fat soluble vitamin that is sounds like a miracle in the research, helping to prevent everything from depression to cancer. It helps you build strong bones by increasing absorption and retention of calcium and phosphorus. It reduces cancer cell growth, helps control infections, and reduces inflammation. Research also found a link between high vitamin D levels and protection from the most severe consequences of Covid-19.

Research has been booming about vitamin D for the last fifteen to twenty years, and startlingly it has shown that roughly 24% of the US population is vitamin D deficient and almost 6% of the population is severely so. Vitamin D deficiency has been implicated in:

  • Autoimmune conditions like lupus and MS
  • Diseases of aging like Alzheimer’s and dementia
  • Mental health issues like schizophrenia and depression
  • Atopic conditions like asthma and eczema
  • Bone diseases like osteoporosis and rickets
  • Hormone issues like PMS and repeat pregnancy loss
  • Inflammatory conditions like IBD and tooth and gum decay
  • Other conditions like cancer, ADHD, and erectile dysfunction

Vitamin D is found in a small number of foods including egg yolk, oily fish, red meat, mushrooms, and liver. The bulk of the vitamin D in your body, however, is produced via a chemical reaction between sunlight and your skin. Specifically, it needs ultraviolet radiation on your skin.

Gene SNPs that Affect Vitamin D Levels VDR Bsm and VDR Taq.

VDR gene SNPs actually code for vitamin D receptors, so this isn’t in the manufacture of vitamin D per se, it’s in the ability to metabolize, transport, and use Vitamin D. There are other gene SNPs that are emerging for Vitamin D, but these are the most frequently studied.

VDR Taq

This gene is associated with both vitamin D levels in the blood and also with muscle growth and bone density on strength training. The CC variant, which is the wild type, is generally linked to high vitamin D levels, as well as greater muscle growth and bone density with strength training exercise. The TT variant, is associated with lower vitamin D status and less muscle growth and bone density in response to strength training. The CT form is somewhere in the middle.

BDR Bsm

This gene is associated with immunoprotection, bone mineral density, and also short stature. The wild type, or GG allele, has lower risk of bone density issues, normal stature, and more typical immunity. The AA allele has a higher risk of bone density problems, is more likely to be short in stature, and may have specific types of immune compromise. The AG allele is somewhere in the middle of those two states.

Managing VDR Gene SNPs

The relationship between these gene SNPs and pathology depends entirely on vitamin D levels, so the clear path to balancing out VDR gene SNPs lies in boosting vitamin D levels. This is where we leave solid research and enter my own musings and supposition, so take this as a well educated guess and nothing more.

The typical “normal” range for vitamin D on blood tests is broad – between 20 ng/mL and 100 ng/mL. Although there is some debate about what constitutes an optimal number, for most people I think hovering somewhere around the 40 – 50 ng/mL mark seems logical. Not too close to the lower limit, but also not pushing crazy high numbers for no reason. For people with VDR polymorphisms, I encourage numbers closer to 70-80 ng/mL simply because if your body has trouble transporting, metabolizing, or using vitamin D, then giving it a higher background level may help to compensate. Again, this is my own supposition and hasn’t been particularly well researched yet.

The complicated relationship between Folate and Vitamin D.

This is actually interesting, because it’s a departure from the usual chemical pathways that we typically talk about. Folate is sensitive to ultraviolet radiation, so the more time you spend with your skin in direct sunlight, especially on high UV-index days, the more folate is used within your skin. This happens because UV light generates free radicals within your skin, and folate acts as an acceptor for those free radicals, essentially doing the duty of an antioxidant in this situation, to help protect your vulnerable tissues from damage.

Folate also works overtime donating methyl groups to DNA that gets damaged by UV radiation, essentially helping to protect your skin from the mutations that would lead to skin cancers.

The bottom line here is that UV exposure uses up folate reserves while UV exposure generates Vitamin D.

There is a remarkable theory of human evolution, the afore mentioned “Folate vitamin D UV-hypothesis of skin pigmentation” that states that skin pigment evolved as humans migrated northward out of Africa to maximize and balance levels of both folate and vitamin D because they are both so pivotal for successful reproduction as well as overall health.

This theory states that skin pigments were concentrated and skin remained dark in areas close to the equator to buffer some of the effects of the tremendous amount of UV exposure, but still allow enough for vitamin D processing. Therefore, people with darker skin pigment actually need more sunlight exposure to manufacture enough vitamin D, and their folate is well protected by the pigments. People who migrated northward were becoming vitamin D deficient due to lack of adequate UV exposure and so evolution favored lighter skin pigments that require less UV exposure to make adequate vitamin D, but that also leave folate more vulnerable to UV-related breakdown.

Vitamin D and MTHFR – A Supportive Relationship?

Because of the contrary relationship between folate and vitamin D with UV exposure, it’s becoming a research target. An interesting study published in the journal neurology, found that in children with ADHD, which has known linkages with both MTHFR and low vitamin D status, the effects of MTHFR on vitamin D weren’t entirely what the researchers predicted.

Children with the C677T homozygous polymorphism (so TT or two mutant copies) actually had higher vitamin D levels than individuals with the CC allele or the “wild type.” Individuals with a heterozygous mutation, or CT allele, were somewhere in the middle.

The researchers theorized that because people with MTHFR need to conserve folate, and therefore need to avoid prolonged UV radiation exposure, they have developed some mechanism to manufacture or maintain vitamin D levels more efficiently.

“As such, individuals with MTHFR TT may manufacture and/or maintain vitamin D more efficiently due to their genetic need to avoid prolonged UVR exposure. Hence, vitamin D levels may be higher at baseline in children with MTHFR TT status.”

Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism and associated vitamin D levels in children with Attention-Deficit/Hyperactivity Disorder (ADHD) (P5.6-043)
Sarah Silverstein, Keith Pecor, Asher Junger, Jeffrey Kornitzer
Neurology Apr 2019, 92 (15 Supplement) P5.6-043;

Thank you so much for listening today.

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The Dangers of UMFA in Pregnancy

UMFA or unmetabolized folic acid is something that has been popping up on research radars more and more frequently in recent years. The combination of food fortifed with folic acid, multivitamin use, the popularity of B complex supplements for energy, and the standard practice of hyper-dosing women with at-risk pregnancies has led to UMFA becoming a common problem. Last week we discussed the remarkable results methyl folate produced in couples with infertility relative to the current standard of care, which is supplementing with folic acid. This week, I’d like to talk about the risks of too much unmetabolized folic acid or UMFA during pregnancy.

First, Let’s Talk Useable Folate

One very wisely designed study published in the American Journal of Clinical Nutrition, compared serum and red blood cell levels of total folate, 5-LMTHF, UMFA, and MeFox which is a methyl folate oxidation product – kind of the 5-LMTHF version of UMFA. The reason I call this study design “wise” is that it gives us a good window into what is actually happening here. Serum levels test the amounts in the fluid part of the blood, which is not yet inside the cells. This isn’t really a functional space for folate – it’s been absorbed digestively, but hasn’t reached useful cellular tissues yet. Red blood cell levels, however, measure the amount that is actually inside of the cell spaces and therefore doing something useful. This study didn’t differentiate between MTHFR or non-MTHFR, or at different forms of folate intake. It simply compares two different doses of folic acid.

One group received about 1.1 mg of folic acid in their prenatal vitamins. The other group received the prenatal vitamin amount plus an additional 4 mg to bring the total to 5.1 mg, or 5100 mcg of folic acid.

What they found in this study, was that the RBC folate level, which is the functional folate, didn’t differ significantly between the two groups. The high-dose folate group did have higher serum levels of total folate, UMFA, and even 5-LMTHF. Other parameters didn’t differ significantly.

The researchers came to the conclusion that there was some kind of tissue saturation happening, where more folate just can’t get into the cells, which makes sense. They also suggest that higher UMFA concentrations in the women receiving the high-dose folic acid indicates that these doses are “supraphysiologic.” That is a fancy way of saying the dose is just too high.

So What is All that UMFA Doing In Pregnancy?

Another study, also published in the American Journal of Clinical Nutrition, studied UMFA levels in cord blood relative to autism spectrum disorder. Cord blood is the blood that remains in the placenta and the attached umbilical cord after delivery.

This study found that babies in the highest quartile of UMFA percentages in the cord blood had the highest risks for autism spectrum disorder. This effect was highest in black babies and significantly correlated with race. This correlation did not apply to the concentrations of 5-MTH or to serum total folate.

Another study, published in the Journal of Allergy and Clinical Immunology In Practice, looked at the association between UMFA levels and food sensitivity and food allergy. This study tested total folate, 5-MTHF, and UMFA levels at birth and again in early childhood.

The researchers found that of 1394 children tested, 507 were found to have food sensitivities and 78 had food allergies. In those children who developed food allergies, the average total folate concentrations at birth were lower and the UMFA levels at birth were higher. Higher UMFA levels later on in childhood didn’t seem to have this same association.

I will quote from the conclusion of this study. “Higher concentrations of UMFA at birth were associated with the development of food allergies, which may be due to increased exposure to synthetic folic acid in utero.”

What To Make Of This?

These are just a few studies and so we really can’t, as much as we might like to, draw sweeping conclusions from them, but it certainly gives us some compelling evidence that too much of what is supposed to be a good thing, can rapidly become a bad thing.

Because we, with MTHFR polymorphisms, are more susceptible to problems associated with folic acid, I think it is important to have an informed and complete conversation with your health care practitioners about the risks of folic acid supplementation in pregnancy for us specifically, and the viable, albeit less well-researched option of supplementing with 5-LMTHF instead.

Links to the research studies I’ve talked about in this podcast are supplied in the complete show notes at tohealthwiththat.com, so if you’re planning a visit to your OB/GYN or midwife, go armed with research to show them.

Thank you so much for listening today and please make sure you’re signed up for our email list – the email list will be the first to know about new courses, programs, and freebies for MTHFR folks.

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The Harm That 5mg Folic Acid Can Do For MTHFR Fertility

This week I wanted to diverge on subjects a bit just because a very relevant question came up in the MTHFR community, This is such an important issue that I want to make sure it gets the attention it deserves.

One of our members in Genetic Rockstars is pregnant and her midwife is recommending 5000 mcg folic acid in spite of her MTHFR issue.  This is a common question because 5000 mcg folic acid is standard practice in many fertility centers and medical offices for pregnancies that are considered in any way at risk.

Like everything else involving MTHFR, research is limited but I do want to deep dive into a couple of relevant studies.

The most important piece of research to take to your midwife or fertility practitioner is a study published in the Journal of Assisted Reproduction and Genetics in 2018.

This study followed 33 couples in which one or both of the partners had an MTHR polymorphism who had fertility problems lasting at least 4 years.  This could include recurrent fetal loss, premature ovarian failure, or abnormal sperm parameters – so bear in mind this could be the mother or the father who has MTHFR issues. Two-thirds of these couples had previously failed assisted reproductive technology attempts.

Most of the women in this study had been previously treated, unsuccessfully, with 5000 mcg (or 5 mg) folic acid.

The couples in this study were given 600 mcg 5-LMTH, which is the active form of folate, for four months before attempting conception or starting another round of assisted fertility treatment. This four-month period was chosen to allow for a complete cycle of spermatogenesis, which is approximately 74 days.

The results of this one simple intervention were, in my opinion, absolutely astounding. Of the 33 couples:

  • 2 were still in treatment at the date of reporting.
  • 13 couples conceived spontaneously (this is after four years of unsuccessful reproductive attempts)
  • 14 achieved successful pregnancies using ART (assisted reproductive technology). ART typically refers to IVF or in-vitro fertilization. 
  • 3 couples did not achieve successful pregnancies.
  • 1 couple failed to report back.

I am going to read the conclusion of this research article verbatim because frankly, I couldn’t sum it up better.

“The conventional use of large doses of folic acid (5 mg/day) has become obsolete. Regular doses of folic acid (100–200 μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800 μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).”

Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet. 2018;35(8):1431-1435. doi:10.1007/s10815-018-1225-2

The most startling result of this research, I feel, is the tremendous number of couples who conceived spontaneously after a simple few-month intervention with 5-LMTHF. Imagine the amount of heartache, expense, and medical intervention that could be avoided if 5-LMTHF became the standard of care?

The other issue considered here is something called Unmetabolized Folic Acid Syndrome, which has been demonstrated in  “wild type” people to cause pseudo-MTHFR. In pseudo-MTHFR, people who have fully functioning MTHFR enzymes have both high levels of unmetabolized folic acid and high levels of homocysteine in their blood. In people with an MTHFR deficiency, UMFA blocks the entry of folates into the folate cycle and further impairs the capacity of their already struggling MTHFR enzymes.

Unmetabolized Folic Acid has also been implicated in promoting colorectal and prostate cancer. And folic acid itself shows poor clinical success and in some cases, it tests worse than placebo in reducing homocysteine levels or downstream measures of cardiac health.

Next week I’d like to talk about some of the issues that have been linked to high levels of unmetabolized folic acid in pregnant mothers and the problems that travel downstream to those unborn children. If you haven’t done so already, please sign up to the email list on tohealthwiththat.com, or join the MTHFR community Genetic Rockstars at community.tohealthwiththat.com. I have big plans this year for courses and I want you to be the first to know.

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