Folate Metabolism, Homocysteine, and Pregnancy

July 27, 2020 Josh MacDonald

What is folic acid?

Folic Acid is the synthetic form of naturally-occurring folate (also called Vitamin B9), which is essential for creating and maintaining cells (e.g. red blood cells), creating and repairing DNA, preventing birth defects, regulating blood homocysteine levels (elevated homocysteine is a risk factor for heart disease), and other vital functions.

Folate deficiency or insufficiency has been linked to neural tube defects, cancer, cognitive dysfunction, and cardiovascular disease. In 1998, the United States began a public health intervention requiring manufacturers to fortify cereal grain products labeled as enriched with 140 mcg of folic acid per 100 grams of flour. These inadequate intakes and levels of vitamin B9 can arise through multiple pathways:

low dietary intake of precursors
poor absorption in the gut
altered folate metabolism due to genetics

Folic acid (also called pteroylmonoglutamic acid) is a synthetic form of vitamin B9 and represents the first molecule in an enzymatic process that creates the bioactive form of folate, called methylfolate or 5-MTHF. This is the form of folate that carries out the vital functions of vitamin B9 in the body.

What is MTHFR?

tldr: The MTHFR enzyme, coded for by the MTHFR gene, makes the conversion from folate precursors (inactive) to bioactive folate (5-MTHF). Mutations (errors) in the MTHFR gene can result in structural changes to the MTHFR enzyme and adversely impact its function. In other words, variations in the MTHFR gene can reduce the conversion of inactive folate into bioactive folate.

The MTHFR gene is the most well-known nutritionally-relevant gene. Genetic variations in this gene can have significant health consequences due to the adverse impact on the efficiency of the MTHFR enzyme. The resulting impeded 5-MTHF production can result in a deficiency of active folate, even in the presence of adequate dietary folates (from food) and synthetic folic acid (typical form in supplements). This interaction is documented by hundreds of studies.

While more than 30 variations have been found in the MTHFR gene, most have insignificant impact on the function of the MTHFR gene. Two notable “single nucleotide polymorphisms” (called SNPs) do significantly impact MTHFR efficiency and have been widely studied. A SNP (commonly referred to as a “snip”) is a type of mutation that occurs when the incorrect nucleotide (the building blocks of DNA) is swapped into the DNA strand. Sometimes, these swaps are completely benign and there are no physiologic consequences. In other cases, these SNPs result in a different amino acid being coded for during transcription, the process of converting genetic information into a protein sequence.

In many biological cases, which is true for this MTHFR example, these common SNPs reduce the processing efficiency of the corresponding enzyme, as the amino acid change slightly alters the structure of the protein. The two aforementioned SNPs in the MTHFR gene reduce the conversion efficiency of 5, 10-methylenetetrahydrofolate (bioactive folate precursor) to the bioactive 5-MTHF (bioactive folate)

Which MTHFR mutations are important?

tldr: In short, SNPs can influence folate activation (inactive folate into bioactive folate) by altering the structure of the MTHFR enzyme.

By far the most studied and impactful SNPs are:

The C677T mutation polymorphism (rs1801133)

This represents a C>T swap mutation at mRNA position 677. This results in the amino acid “alanine” being swapped with “valine” in the protein product at position 222.

The A1298C polymorphism (rs1801131)

This represents an A>C swap mutation at mRNA position 1298. This results in the amino acid “glutamic acid” being swapped with an “alanine” in the protein product at position 429.

When most people discuss the MTHFR gene, they are referring solely to the C677T mutation. It is the most studied and impactful SNP in terms of MTHFR function. At Rootine, we go a step further and we test and analyze both the C677T and A1298C mutations and include both data points in our determination of your folate requirements. It is important to note, only ~15% of the population carry neither mutation. For this reason, it is clear that variations in the MTHFR gene are incredibly common and that each person has a unique ability (or inability) to process folate.

tldr: Two mutations in the MTHFR gene have a significant impact on the activity of the enzyme. The C677T polymorphism typically reduces conversion efficiency by approximately 35% per copy and A1298C reduces conversion by approximately 20% per copy.

The inheritance patterns are as follows:

“wild-type” (no mutations in MTHFR gene)
one or two copies of the C677T mutation
one or two copies of the A1298C mutation
one copy with C677T and one copy with A1298C mutations.

When considering these two common polymorphisms and other lifestyle factors, a spectrum of folate conversion is present from a populationational view. For simplicity, the population distribution can be roughly grouped into quintiles by conversion efficiency, compared to the wild-type:

A common misunderstanding

tldr: Folic acid is not inherently bad, contrary to popular belief. Accumulation of “unmetabolized” folic acid is a concern but does not occur due to MTHFR gene mutations.

Due to the high prevalence of MTHFR gene mutations and the important role that bioactive folate plays in human health, “folic acid vs. folate” supplementation has become an incredibly contested topic. Many misconceptions exist, especially around folic acid supplementation.

The primary contention revolves around “unmetabolized folic acid,” abbreviated UMFA. Concern arises due to folic acid remaining in its synthetic, inactive form (not undergoing enzymatic change to eventually become 5-MTHF) and circulating or accumulating in the body. The common assumption is that genetic variations in the MTHFR gene in the MTHFR gene lead to inefficiencies in the folic acid conversion pathway, and thus lead to accumulation of UMFA in the blood of these individuals. This is incorrect.

While high levels of UMFA can accumulate in the blood and can be dangerous; this has nothing to do with the MTHFR enzyme. The MTHFR enzyme is the last step in the conversion process and does not interact with folic acid. Thus, MTHFR mutations will only lead to elevated levels of 5, 10-methylenetetrahydrofolate, which is the substrate for the MTHFR enzyme.

How we handle folate at Rootine

tldr: The prenatal formula has a folate baseline of 800mcg DFE and dosing increases based on blood and DNA data up to 1000 mcg DFE. The total dose is split between folic acid and methylfolate depending on your specific MTHFR activity.

For prenatal formulas, there is a baseline of 800 mcg DFE of folate. Folate is supplied in the form of folic acid and methylfolate, form dependent on the activity of the MTHFR enzyme determined by the genotypes of rs1801133 and rs1801131.

For individuals with impaired folate metabolism due to MTHFR mutations or identified by the blood test, additional folate is added to the user’s formula, up to 1000 mcg DFE.

Why we chose this method

There is much nuance around the MTHFR gene, folate dosing, and the various forms of folate available. Many people ask why we include folic acid at all, when many brands provide exclusively methylfolate. It’s important to remember that MTHFR gene mutations do not inactivate the enzyme, they just slow the conversion. Even in the worst case (homozygous T677T mutations) the enzyme still works and folic acid is still an option.

Some people do not respond well to large influxes of methylfolate, especially if they are starting at impaired folate status. By splitting the dose between folic acid and methylfolate, we provide a more “gentle” experience and alleviate the negative side effects that a segment of the population would experience from high-dose methyl folate.

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