Folic Acid Supplements and Genetic Polymorphisms


Breads and other products such as breakfast cereals are often fortified with various vitamins and minerals. There has been a recent concern that many gluten free products do not receive such fortification and perhaps the allergy free consumer is missing out.
Nutritionist Christine Bailey
who regularly runs genetic testing on clients offers some insight into the folic acid fortification debate.

Breads and other products such as breakfast cereals are often fortified with various vitamins and minerals. There has been a recent concern that many gluten free products do not receive such fortification and perhaps the allergy free consumer is missing out. Recently certain manufacturers have addressed this by fortifying certain products such as gluten free with vitamins such as folic acid. While many consumers feel this is valuable some consumers are concerned about how using synthetic forms of supplementation may affect them if they have known genetic polymorphisms. 


When we talk about the role of folate in nutrition it is important to first clarify terminology.

The term folate is typically used as a generic name for the group of chemically related compounds based on the folic acid structure.

Folate, or vitamin B9, is thought of as one of the 13 essential vitamins. It cannot be synthesized de novo by the body, and must be obtained either from diet or supplementation. Dietary folate is a naturally occurring nutrient found in foods such as leafy green vegetables, legumes, egg yolk, liver, and citrus fruit.

Folic acid is a synthetic dietary supplement that is present in artificially enriched foods and pharmaceutical vitamins. Neither folate nor folic acid is metabolically active. Both must be reduced to participate in cellular metabolism. l-5-Methyltetrahydrofolate (l-methylfolate) is the predominant micronutrient form of folate that circulates in plasma and that is involved in biologic processes.

The importance of folate

We all probably all aware of the importance of folate for health – particularly during pregnancy to help prevent certain neural defects. However folate is also important for numerous body processes including maintaining healthy red blood cells, reducing the risk of preterm babies and is vital for the production of key neurotransmitters that affect how we think and feel. This includes serotonin: low levels of which are associated with low mood and depression.

Folate is vital for methylation in the body. Methylation is a key biochemical process that is essential for the proper function of almost all of your body’s systems. It occurs billions of times every second; it helps repair your DNA on a daily basis; it controls homocysteine (an unhealthy compound that can damage blood vessels); it helps recycle molecules needed for detoxification; and it helps maintain mood and keep inflammation in check.

Folic Acid Metabolism in the Body

To become metabolically active, folic acid must first be converted to dihydrofolate (DHF) and then tetrahydrofolate (THF) through various enzymatic processes. THF can be converted to the biologically active l-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR) and it is variations in the activity of this enzyme that has raised concern for some consumers.

MTHFR is the critical enzyme for almost all biologic processes that involve the metabolism of folate and methionine. Genetic variations in the MTHFR are common. There are two common polymorphisms known as A1298C and 677CT. It is estimated that 60% of the population are intermediate metabolizers of folate or what we refer to as heterozygous for genetic polymorphism of the MTHFR enzyme whereas up to 25% of certain populations are homozygous for these genetic variations. 

In varying degrees, these polymorphisms impair the conversion of folate to its active form, l-methylfolate.  This potentially means if you have a polymorphism and you ingest folic acid in supplementation form you may struggle to convert it to its active form which is L methylfolate. This can actually lead to a build up of unmetabolised synthetic folic acid.   It is therefore not surprising then that research has shown that supplementation with l-methylfolate was more effective than folic acid at increasing red blood cell folate concentrations. 

The only real way to know if you have one of these polymorphisms is to do a DNA test which is a simple swab taken from your mouth. There are many health concerns where testing for methylation SNPs such as MTHFR will be relevant. This may include those trying for a baby (preconception care), infertility, neurological disorders, cancer, cardiovascular risk, drug sensitivities, chronic pain, histamine, Autism, MS, Alzheimer’s, Depression, insomnia, neuropathy and anxiety.

Supplementation with l-methylfolate

Based on the high prevalence of MTHFR genetic polymorphisms in the general population and concerns about reduced enzymatic activity and, therefore, less biologically available l-methylfolate, newer research in this area has focused on supplementation with l-methylfolate rather than folic acid as a means of preventing folate-related pathology.

In a recent double-blind, randomized, placebo-controlled trial of 144 women of childbearing age, Lamers and colleagues demonstrated that supplementation with l-methylfolate was more effective than folic acid at increasing red blood cell folate concentrations. (1)

Concerns over high dose folate supplementation

Although folic acid supplementation has demonstrated many of the benefits to pregnant women there is a concern about high-dose folate supplementation.  First, folate supplementation can mask vitamin B12 deficiency (pernicious anemia). There are also concerns about potential untoward effects of unmetabolized synthetic folic acid with regard to cancer, depression, and cognitive impairment.  With all these concerns, early data suggest supplementation with l-methylfolate rather than folic acid may mitigate these risks and prove more beneficial to a wider number of people. Of course this form may prove too expensive to use widely in foods but it is now readily available in supplement form.

What if you have a MTHFR genetic polymorphism

So what if you know you have a MTHFR genetic polymorphism – should you consume synthetic folic acid? 

Firstly remember that for biological processes such as methylation there are numerous enzymes involved and many other vitamins and minerals so ideally work with a practitioner who understands all the biochemical processes involved. Simply looking at the MTHFR polymorphisms and folic acid on its own will not necessary provide you with the full picture or help your health long term. 

There are also other factors that also influence your levels of active folate as well so consider these in addition to whether you should eat fortified foods.

  • Poor diet – The word “folate” comes from “foliage.” You need to eat plenty of leafy greens, beans, fruit, and whole grains to get adequate levels of vitamins B6 and B12, betaine, and folate which are all important in methylation. Egg yolks, meat, liver, and oily fish are the main dietary sources of vitamin B12 — so long-term vegan diets can be a problem. Plus, certain compounds can raise levels of homocysteine and deplete the B vitamins. These include excess animal protein, sugar, saturated fat, coffee, and alcohol as well as smoking.
  • Malabsorption - Conditions like digestive diseases, food allergies, and even aging can reduce absorption of nutrients
  • Decreased stomach acid – Aging and other conditions can reduce stomach acid — and therefore absorption of certain vitamins linked to methylation like B12
  • Medications – Drugs like acid blockers, methotrexate (for cancer and arthritis and other autoimmune diseases), oral contraceptives, HCTZ (for high blood pressure), and Dilantin (for seizures) can all affect levels of B vitamins

What to do

Check any multi vitamins and mineral supplements you are taking – this may be far more significant than the odd slice of fortified bread. Are you consuming high levels of synthetic folic acid or is it already in the L methyl form?

If you do have particularly a homozygous polymorphism, then utilizing synthetic folic acid will be compromised but whether consuming the occasional bowl of fortified cereal is a concern will clearly depend on so many other factors linked to your current health, diet and lifestyle and the many other related genetic polymorphisms you may have.

For health we would always recommend focusing on real food anyway – not processed or refined foods with plenty of colourful vegetables, leafy greens, lean protein, healthy fats and some gluten free grains.

  1. Lamers Y, Prinz-Langenohl R, Brämswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84:156–161. 
  2. Wilcken B et al. J Med Genet 2003 40: 619-625 Geographical and ethnic variation of the 677CT allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide.
  3. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr. 2010;91:1733–1744.
  4. Frankenburg FR. Folate supplementation: is it safe and effective? J Clin Psychiatry. 2009;70:767.

If you would be intersted in lear gn more about DNA testing for MTHFR genetic polymorphism, contact Christine here.

February 2017

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