There is a lot of talk online about MTHFR variants and the need to avoid folic acid. I’m digging into the topic a bit and see what is found in research studies, as well as look at the history of folic acid supplementation. Then I will go into some of the research studies on MTHFR, DHFR, and SLC19A1 variants.

How the body breaks down folic acid…
Folic acid is a synthetic form of folate that is temperature and pH stable, allowing it to easily be added to processed foods and multivitamins.  The chemical name for folic acid is pteroylmonoglutamic acid or PteGlu.

A 2014 review in Preventive Nutrition and Food Science thoroughly explains the breakdown of folic acid:

“However, since PteGlu is not a natural form of folate, it requires additional metabolic steps before it can enter the circulating plasma folate pool as 5-methyltetrahydrofolate (5-CH3H4PteGlu). In order to enter folate metabolism, PteGlu needs to be reduced first to dihydrofolate (H2PteGlu) and then to the active form, tetrahydrofolate (H4PteGlu) which is the methyl group shuttle required for the de novo synthesis of purine, thymidylate and methionine. This additional step is exclusively mediated by dihydrofolate reductase (DHFR) (33). The main role of DHFR is to catalyse the reduction of H2PteGlu to H4PteGlu. It is also responsible for the conversion of PteGlu to H2PteGlu, but with a higher Km. In addition, H2PteGlu allosterically modulates the activity of methylenetetrahydrofolate reductase (MTHFR) which is one of the key enzymes of folate metabolism (34). Therefore, DHFR is critical for both the continuous circulation of reduced folate in the body and synthetic PteGlu metabolism “

Another study in 2012 explains the concerns with un-metabolized folic acid:

There is much debate as to whether exposure to unmetabolized folic acid poses a health risk [17]. Theoretically, folic acid could interfere with normal folate metabolism through competition with reduced, coenzymatic folates for transporters, binding proteins, and folate-dependent enzymes [18–20]. For instance, both folic acid and H2PteGlu are substrates for DHFR. Although the affinity of DHFR for H2PteGlu is higher than its affinity for folic acid, in the presence of high concentrations of folic acid, folic acid could competitively inhibit the conversion of H2PteGlu to H4PteGlu [19]. As neither folic acid nor H2PteGlu is metabolically active, this could theoretically create an intracellular folate deficiency [19]. Another study observed a downregulation of folate transporters in intestinal and renal epithelial cells cultured in growth media that were oversupplemented with folic acid

A study from 2007 looked at the dosage at which un-metabolized folic acid would appear in the bloodstream.  This study was completed in the UK, which had not mandated fortification of flour, so the participants had no unmetabolized folic acid in their bloodstream prior to beginning the study.  The study concluded: “Based on the cumulative evidence to date in this and other studies [4-6] it seems that the threshold dose above which unmetabolised folic acid appears in serum lies around 200 μg. The intervals between repeated exposures also seem to be an important factor [6] as an accumulative effect is observed if repeated doses are consumed close together. These are important considerations for policy makers planning an intervention.” [ref]

Finally, a 2012 study looking at the effects of supplementing with either 1.1mg or 5 mg of folic acid found that there is a great variation in people’s capacity for metabolizing folic acid.[ref]

Genetic Variants Related to Folic Acid Metabolism

DHFR – Dihydrofolate reductase

The DHFR gene codes for the enzyme that converts dihydrofolate (from folic acid or folate) into tetrahydrofolate.

rs1677693 (the minor allele is C)

  • A 2010 study looked at the risk of colon cancer based on DHFR genotype in a ‘post-fortification’ era.  It found that rs1677693 (C allele) was associated with a decreased risk of colon cancer.  [ref]
  • Another 2010 review also looked at DHFR in relation to colon cancer.  It also discusses the lower risk of colon cancer for carriers of the variant, especially in those who didn’t supplement with multivitamins.   [ref]

rs1643649 (the minor allele is C)

  • A study showed the minor allele increased susceptibility to spina bifida.  [ref]

rs1650697 (the minor allele is A)

  • A 2010 study found that in a Chinese population the minor allele gave a slightly more favorable prognosis for nonsmall cell lung cancer.  [ref]

rs1232027 (the minor allele is G) (v.4 and v.5)

  • A study from 2010 found that this variant gave and OR=2.99 as far as response to methotrexate (cancer drug that suppresses folate metabolism). [ref]


MTHFR is a well researched and much talked about variant.  (See my post on MTHFR if you need to check your 23andMe data)  While at first glance it may seem that those with MTHFR 677 and 1298 variants may gain some kind of benefit from folic acid as long as their DHFR gene is working well, more studies need to be done to determine if unmetabolized folic acid negatively affects those with MTHFR variants.

A 2014 mouse study found that mice bred to be Mthfr +/- had liver issues consistent with non-alcoholic fatty liver disease when fed a diet high in folic acid (10 fold higher than recommended).

Another recent study showed that, regardless of MTHFR status, [6S]-5-MTHF (methyl folate) had higher bioavailability than folic acid.[ref]

SLC19A1 – folate transporter gene
This gene is responsible for making the protein that transports folate compounds into the cell.[ref]

rs1051266 (T is the minor allele)

  • The minor allele is associated with reduced plasma folate levels.  [ref]
  • The minor allele  increased the risk for colon adenoma for those with MTHFR 677C, but decreased the risk for those with MTHFR 677TT (minor allele) [ref]

Linking folic acid to autism…
A study in May 2016 found that high levels of folate in the mother after birth doubles the risk of autism for the child. The combination of high B12 and high folate levels gave an even greater risk. Here is an article about the study: Excessive Folate, B12 in Pregnancy Dramatically Ups Autism Risk. 

Other studies in the past have found that prenatal vitamins (most likely with folic acid) reduced the risk of autism, especially in those with MTHFR677 TT.[ref]  More studies are needed to determine what, if any, role folate metabolism plays in Autism.

Other interesting studies…

  • Preterm births: A 2014 study looked at 66,014 Norwegian mothers and risk of spontaneous preterm delivery.  It found “The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for spontaneous PTD (HR 1.18; CI 1.05-1.32) compared to no folic acid supplementation preconception.” [ref]
  • Prostate cancer: A 2009 randomized placebo-controlled trial for colorectal adenomas found that folic acid supplementation (1 mg/day) more than doubled the risk of prostate cancer.  “Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01).” [ref]
  • Weight gain: A recent rat study found that excess folic acid along with a higher fat diet caused increased weight gain and inflammation. [ref]

History of how Folic Acid came to be supplemented in the US

Widespread folic acid fortification began in the US in 1996 and then became mandatory in 1998. It is currently added to all “enriched bread, flour, cornmeal, rice, pasta, and other grain products”. [ref]  This mandate was made to reduce the risk of neural tube defects, which happened at the rate of  2,500 babies with NTD/year in the US in 1992. A 2015 CDC article claims: “The birth prevalence of NTDs (proportion of babies in the population born with an NTD) has decreased by 35% in the United States since folic acid fortification was required in 1998.”   [ref]

The history of the FDA decision to mandate fortification with folic acid is interesting to read.  It states that:
Folic acid fortification, for all practical purposes, was not even on the regulatory horizon when it was first included in the 1990 Nutrition Labeling and Education Act (NLEA). FDA scientists at the time felt that the charge to consider the link between folic acid and neural tube defects literally came “out of the blue.” Later, they concluded it probably started with a science workshop hosted by CDC in the late 80s in which unpublished data on folic acid and neural tube defects were presented and seized upon by the supplement industry.” The article goes on to explain that a British study published in 1991 showed that women who already had a child with neural tube defects reduced their risk of having a second child with NDT when they supplemented with 4 mg of folic acid per day. This study was in contrast to the FDA contracted report in 1991 which stated that studies had failed to show the connection between folic acid and NTD.

By August of 1992, the FDA is changing its stance on folic acid.  The article goes on to say:

“In August and September 1992, FDA reviewed results obtained from two additional, unpublished studies, and worked closely with authors and journals publishing them to ensure that the results were made public early. The first, a Hungarian research study, showed a reduced risk of ntd’s in women consuming .8 mg. of folic acid as part of a multivitamin/mineral supplement. The study had been conducted with a sample of women in the general population without a previous history of an ntd pregnancy. The second study was a case control study of women in the general population of Boston, Toronto, and Philadelphia and was referred to as the “Werler study.” This study suggested that .4 mg. of folic acid daily from multivitamin/mineral supplements was associated with a reduced risk of ntd. It also suggested that a diet adequate in folate with more than .25 mg. daily was protective. The new preponderance of scientific evidence on folic acid created a platform from which the Public Health Service (PHS) spoke on September 14, 1992. PHS formally recognized the link between folic acid intake and ntd’s as a compelling public health issue. It recommended that all women of childbearing age should have adequate folate intakes (.4 mg. daily) throughout their childbearing years, but warned that the total intakes should not exceed 1 mg.”

The Werler study that the FDA used for their recommendation looked at 436 cases of NTD with a control group of 2615 babies that had other birth defects. The study threw out 17% of cases and 3% of controls because they knew about the hypothesis that folic acid prevented neural tube defects.  Then they based the conclusion on the reported use of daily multivitamins that also contained folic acid. I admit that I am confused by this study, specifically by why the control group was only babies with birth defects and how the conclusion was reached that it was the folic acid in the multivitamin that lowered the risk of NTD. I’m also unclear as to why you would throw out 17% of the cases because they knew to supplement with folic acid. That seems like it would skew the data.

I found a copy of a second study by the same author, Martha Werler, on on the Oxford Journal website published a few years later using the same study population, I think. The study group consisted of 303 babies with oral clefts while the control group was 1,167 babies who had other birth defects not related to oral clefts or neural tube defects. The study talks about how neural tube defects and oral clefts are related and then broke the data down by the number of mothers supplementing with multivitamins before and during the first trimester.  The study’s conclusion reads “We found no significant protective effect for folic acid supplementation in relation to the risk of all oral clefts, cleft palate, or cleft lip with or without cleft palate.

Please don’t get me wrong…  I am not questioning a link between NTD and folate levels, but rather I’m surprised at how little data the FDA used in making the decision to force the fortification of folic acid on the public. I had rather naively assumed that there were lots of good studies showing without a doubt that 400 μg/d  of folic acid was exactly what we all needed.

Colon cancer and folic acid
Colon cancer rates increased around the same time that fortification programs for folic acid began.  Of course, correlation doesn’t equal causation, and the rise in colon cancer rates could be due to another factor.  Except– several studies link folate status to colon cancer, and inhibition of DHFR via pharmaceuticals is one method of slowing certain cancer.  Also, the MTHFR 677-TT variant which impairs the enzyme’s activity also decreases the risk of colon cancer. [ref] [ref]

A 2007 article in the journal Cancer Epidemiology, Biomarkers & Prevention sums up the correlations between the increase in colon cancer and the implementation of folic acid fortification:

“There is a very close chronological relationship between these increases in the incidence of CRC and the remarkable increase in systemic folate status that occurred among adults as a result of folic acid fortification. As mentioned above, both countries experienced approximately a 100% increase in plasma folate levels between 1996 and 1999 (5, 6).” …. “Although mandatory fortification did not begin until 1998, it is important to recall that voluntary fortification in the United States began almost immediately after the March 1996 report. Voluntary fortification began somewhat later in Canada because the legislation did not allow for it until December 25, 1996. Thus, the increase in the incidence in CRC in each country was nearly contemporaneous with the increase in dietary folic acid intake and blood folate level.”  [ref]

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Building Up Iron – Genetics, Diet, and Health Effects | Genetic Lifehacks · April 12, 2017 at 7:10 pm

[…] for some men and older women.  When looking at the forced fortification of foods with iron and folic acid, it really does seem that the policymakers are focused on the majority, at the expense of a […]

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