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MTHFR Mutation: What is it? How to check your raw data.

Key takeaways:
~ The MTHFR gene impacts how your body utilizes folate (vitamin B9).
~ Folate is needed to create methyl groups, which are used to synthesize neurotransmitters, detoxify toxicants, methylate DNA, and maintain a healthy heart.
~ The MTHFR C677T and A1298C variants impact how well the gene works and can cause high homocysteine levels.
~ You don’t need expensive testing for MTHFR; you can check your C677T and A1298C SNPs in 23andMe or AncestryDNA data.
~ Optimizing your diet and nutrient intake is an easy way to improve overall wellness and stay healthy as you age.

What is the MTHFR gene?

MTHFR is a central gene in the methylation cycle and is a limiting factor for producing methyl groups from folate (vitamin B9).

Common genetic variants, called MTHFR C677T and A1298C, affect how the enzyme works and impact the availability of methyl groups. Genetic variants are variations in the DNA sequence that can influence the function of a gene or the protein it encodes.

Specifically, the MTHFR gene codes for an enzyme called methylenetetrahydrofolate reductase that turns folate into the active form, 5-methyltetrahydrofolate. This enzyme, along with the active form of vitamin B-12 (methylcobalamin), drives an essential portion of the methylation cycle.

I’ll go into more detail on this in the next section.

First, check your MTHFR variants below so that you can apply the information in the rest of this article. The MTHFR C677T and A1298C variant information is available in 23andMe and AncestryDNA raw data.

Genotype Report: MTHFR C677T and A1298C

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Not a member? Join Here. Membership lets you see your genotype in articles and gives you access to the members-only information in the Lifehacks sections.

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: typical *
  • A/G: one copy of MTHFR C677T allele, enzyme function decreased by 40%
  • A/A: two copies of MTHFR C677T, enzyme function decreased by 70 – 80%[ref]

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):

  • T/T: typical *
  • G/T: one copy of MTHFR A1298C (heterozygous), slightly decreased enzyme function
  • G/G: two copies of MTHFR A1298C (homozygous), decreased enzyme by about 20%

Members: Your genotype for rs1801131 is .

 

OK – now that you know your  MTHFR C677T and A1298C genotypes, let’s dig into the details of what all of this means.

The MTHFR C677T and A1298C variants:

The MTHFR C677T variant is a single nucleotide polymorphism (SNP). A SNP is a variation in a single nucleotide base pair (the As, Cs, Gs, and Ts) that differs from the typical nucleotide at that spot in the gene for part of the population. Similarly, A1298C is another SNP in the MTHFR gene.

Both MTHFR C677T and MTHFR A1298C are common variants (SNPs). Both polymorphisms are found in around half the population. The changes make the MTHFR enzyme function a little bit differently.

For the MTHFR C677T variant, the changed nucleotide causes a change to the protein structure that makes the enzyme break down faster at normal body temperature (called thermolabile). This faster enzyme breakdown reduces the amount of enzyme available in each cell when folate is limited.[ref][ref][ref]

One copy of the C677T variant reduces enzyme function by about 35-40%, while individuals with two copies (homozygous) have about a 70% reduction in enzyme function. The A1298C variant has less of an impact, with two copies decreasing enzyme function by around 20%. [ref]

Here’s why MTHFR is important…

MTHFR and the methylation cycle:

The MTHFR gene encodes an enzyme that is a key part of the methylation cycle.

Methylation is the addition and removal of a methyl group (-CH3) to amino acids, DNA, and other enzymes or proteins. Within the methylation cycle, folate can be used to donate a methyl group that is used by SAMe for methylation reactions. This is a cycle that also involves homocysteine (which we will come back to in a minute).

Methyl groups are used to:

  1. Form new molecules, including neurotransmitters
  2. Control DNA gene expression (turn on and off genes)
  3. Detoxify certain substances

Let’s look at each of these:

1. Forming new molecules:
Most of the molecules in our body are chains of hydrocarbons — carbons plus hydrogens. So adding a methyl group, a carbon plus three hydrogens, stacks on one more link in a hydrocarbon chain. The methyl group changes the original molecule into something different. A methyl group makes the molecule non-polar, which means that it isn’t able to mix with water and instead can pass through lipid membranes more easily.

Let’s take the synthesis of melatonin as an example:
A methyl group is added to serotonin in the two-step process that forms melatonin.

The ASMT enzyme adds a methyl group to N-acetyl-serotonin to form melatonin.

 

2. DNA methylation:
DNA methylation is the addition of a methyl group to specific locations on a chromosome. By binding to these spots, methylation can turn genes on and off, and maintain and repair your DNA. This is an ongoing, essential, and continual use of methyl groups.

3. Detoxification and breaking down substances:
Methylation is essential in the nervous system, in the production and breakdown of neurotransmitters, and in detoxifying some specific environmental toxicants such as arsenic.

The folate and methylation cycle is a series of biochemical reactions that involve the transfer of methyl groups. For those who like a visual pathway, here’s what the complete folate and methylation cycle looks like. Notice that MTHFR is in a key spot.

Members: Download a .pdf of this and other pathways in the Pathway Planners section.

Research studies on MTHFR C677T or A1298C variants

The MTHFR gene is one of the most well-researched genes, with over 6,000 studies investigating the C677T variant.

Having an MTHFR variant increases the relative risk of many chronic diseases, but this does not mean it will cause you to have that disease. 

Simply put, these variants increase susceptibility to chronic disease in combination with diet and lifestyle factors. Importantly, dietary changes or supplemental vitamins can eliminate many of the problems from the MTHFR variants.

Studies show that the C667T and A1298C variants increase the risk of numerous health conditions:

  • high homocysteine levels, stroke risk, and heart disease[ref][ref][ref]
  • neural tube defects (spina bifida) and cleft lip[ref]
  • stroke[ref][ref]
  • preeclampsia and hypertension in pregnancy[ref][ref]
  • miscarriage[ref][ref]
  • depression or anxiety[ref][ref][ref][ref][ref]
  • rare problems with nitrous oxide – very uncommon, affects B12 levels[ref] (most have no problems with laughing gas[ref])

 

Let’s go a little more in-depth on the studied effects of MTHFR SNPs.

Symptoms of MTHFR variants:

1. Depression and the MTHFR Gene Variants:

A meta-analysis of 26 studies found that the MTHFR C677T variant was associated with an increased risk of depression.[ref] Age and gender may also play a role here. Postmenopausal women who carried the C677T variant had a 2 to 3-fold increased risk of depression.[ref]

Women with two copies of the A1298C variant were at twice the risk of major depressive disorder (MDD). The risk of MDD was even higher in COMT slow (MET) allele carriers. (read about COMT)[ref]

Not all studies agree, and some studies show that the MTHFR C677T variant has little to no impact on depression risk. The difference could be due to diet. People who eat a diet that includes more folate (green vegetables, legumes, liver) may not be at an increased risk of mood disorders, while people who eat few folate-rich foods may be more susceptible to depression.[ref][ref]

Related article with more details: MTHFR: depression and anxiety

2. High Homocysteine  with MTHFR variants:

The methylation cycle also controls the level of homocysteine, an important marker of heart disease risk. It is also involved in cholesterol levels.[ref]

Genetic variants in the methylation pathway, including MTHFR, are strongly linked to high homocysteine levels and heart disease in many studies. High homocysteine is also linked to increased blood clots.[ref][ref][ref][ref]

Related article: Homocysteine- Genetics and Solutions

3. Increased risk of heart disease

Extensive studies show a link between MTHFR C677T and an increased risk of cardiovascular disease. For example, a meta-analysis found that two copies of the MTHFR C677T variant (A/A, homozygous) increase the relative risk of heart disease by 38%.[ref] The increased risk of heart disease is often explained as being due to high homocysteine levels in people with the MTHFR variant who don’t get adequate folate.[ref]

New research published in 2022 shows that people with the C677T variant (AG or AA) have reduced endothelial function, even when homocysteine levels are normalized by increasing folate intake. Endothelial function refers to the ability of the blood vessels to dilate and contract to control blood pressure. The endothelium is the lining of blood vessels, and endothelial function controls how the blood vessels relax or contract to control blood pressure.[ref][ref]

Related article: MTHFR, riboflavin, and reducing high blood pressure

4. Pregnancy, infertility, and MTHFR:

One of the first researched links to MTHFR variants was for neural tube defects. Babies need folate for the spinal column to develop fully, and the MTHFR variants increase the risk of problems.[ref] This is why prenatal vitamins contain folate and why folic acid is added to white rice and white flour.

Related article: MTHFR, pregnancy, and infertility

5. Break down of estrogen, interaction with histamine:

Additionally, the methylation pathway involves the regulation of hormones, such as estrogen, as well as playing a role in histamine levels.

Related article: Histamine metabolism and estrogen receptors

6. Migraines

Numerous studies show that MTHFR variants are linked to a significantly increased risk of migraines.  Some studies indicate that the risk is also due to higher homocysteine levels[ref], while other studies show that it may be due to the methylation of certain genes.[ref]

Meta-analyses showed that the MTHFR C677T variant increased the risk of migraines with aura for all population ancestry groups. In non-Caucasians, the C677T variant increased migraine risk by 3-fold.[ref][ref] In North Indians, the A1298C variant was associated with the risk of migraines.[ref]

Related article: Getting to the root genetic cause of migraines

7. Detoxification and MTHFR

A methyl group is needed in the detoxification reaction for arsenic. The enzyme (arsenite methyltransferase) that metabolizes arsenic depends on the availability of methyl groups. The C677T variant is linked to decreased arsenic detoxification and increased skin lesions with exposure.[ref][ref]

Related article: Arsenic detoxification genes

Additionally, methylation is important in detoxifying mercury. In fact, MTHFR variants are tentatively linked to being more likely to have problems detoxifying mercury (small study).[ref][ref]

Related article: Mercury detoxification genes

Tradeoffs! Positive benefits of MTHFR SNPs

You may wonder why MTHFR variants with such negative effects are so common in all population groups. It seems like a variant that should have been weeded out with natural selection. One thing I’ve noticed is that for common negative variants, there is almost always a positive effect that balances it out. Let’s explore the potential positive benefits of MTHFR SNPs.

The big positive for MTHFR C677T is that it protects against several common types of cancer. Folate is needed for cell growth, especially fast-dividing cancer cells, and the decrease in folate with MTHFR variants can protect against growth in fast-growing tumors.

Studies finding protective effects against cancer:

  • A meta-analysis found that two copies of the C677T variant (AA genotype) decrease the risk of colon cancer by about 20%![ref]
  • Another meta-analysis found that two copies of the C677T variant (AA genotype) were protective against prostate cancer.[ref]
  • The MTHFR C677T variant decreases the relative risk of retinoblastoma and oral squamous cell cancer.[ref][ref]
  • Another study found two copies of the C677T variant (AA genotype) were protective against gastric cancer.[ref]

The MTHFR A1298C variant (GG or GT) is associated with a decreased risk of hypothyroidism.[ref]

The flip side: Folate can also help protect against cancerous mutations in the first place. A lack of folate is linked to double-strand mutations in DNA replications. If those mutations occur in a gene important to cancer prevention, then a tumor can occur.[ref] Thus, folate helps to prevent the mutations that cause cancer, but yet in someone who has cancer, folate and methyl groups can fuel cancer cell growth.

 


Lifehacks: Diet and Supplements for MTHFR

Knowing that you carry an MTHFR genetic variant can help guide your choice of foods and supplements. By optimizing your diet, you can easily mitigate the risks from the MTHFR variants.[ref]

Let’s explore some diet and supplement options for individuals with MTHFR variants.

Diet for MTHFR:

Increase folate-rich foods:
The RDA for folate is 400 mcg/day. Increasing your intake of folate (vitamin B9) from foods will help mitigate some of the risks from the MTHFR variant.

Folate-rich foods include dark leafy greens, lentils, liver, asparagus, and broccoli.

Is increasing dietary folate enough?
Yes, according to studies. For example, a recent study showed that simply increasing folate-rich foods reduced homocysteine levels and inflammatory markers in women with the MTHFR C677T variant.[ref]

Related article: Folate-rich foods and recipes for MTHFR

Folic acid is not the same as natural folate:
Not everyone processes folic acid, the synthetic form of vitamin B3, the same way. People with DHFR genetic variants, especially in conjunction with MTHFR variants, may want to avoid overconsumption of folic acid because it can build up as unmetabolized folic acid.

Related article – check DHFR genes: Folic acid and your DHFR gene

Increase your dietary choline intake: 
Choline can help your body bypass a lack of folate in the methylation cycle.[ref][ref] Good sources of choline include egg yolks, beef liver, and wheat germ. A type of choline called betaine (TMG) is what works through the methylation cycle. Food sources of betaine include beets, quinoa, and spinach, and are also helpful for optimizing the methylation cycle.

Related article: Choline-rich foods and recipe ideas

Supplements for MTHFR:

If your diet doesn’t provide enough of the nutrients needed in the methylation cycle, you may want to consider supplements to increase your intake.

Methylation cycle supplements include:

  • Methylfolate
  • Vitamin B12 (methylcobalamin, hydroxocobalamin, or adenosylcobalamin)
  • Riboflavin
  • B-complex
  • Creatine
  • Choline

Let’s dig into the details of these:

Supplemental methylfolate + vitamin B12:

  • Methylfolate: If you aren’t getting enough folate from foods, methylfolate is available as a supplement. Methylfolate is the active form of folate (vitamin B9).
  • Vitamin B12 is also important in the methylation cycle, so you need to ensure you are getting enough B12 either through your diet (animal-based foods) or supplements. The ability to absorb B12 from the diet often decreases in aging, so supplemental forms may be a good option in older adults. (Also check your Vitamin B12 genes)

How much methylfolate?
Keep in mind the RDA for folate is 400 mcg for adults (800 mcg for pregnancy). Many methylfolate supplements provide a lot higher dose than the 400 mcg recommended  Methylfolate is equivalent in absorption and utilization to folic acid at low levels, but at higher levels, it is thought to be utilized better, and thus not as much may be needed.[ref] You may want to be cautious with higher doses, due to folate being needed for cancer growth.[ref]

  • Always keep in mind that you can take just part of the methylfolate tablet or capsule if you buy one that provides an excessive dose for your situation.
  • Some psychiatrists prescribe high doses of methylfolate for specific mental health issues.
  • Talk with your doctor if you have any questions about prescriptions and supplements.

Side effects from methylfolate or methylB12:

Some people may find that methylfolate makes them irritable, irrationally angry, or anxious due to rapid changes in their neurotransmitter levels. People with the slow COMT genetic variant may want to be careful about high-dose supplements that affect the methylation cycle, such as methylfolate and methyl B12 (methylcobalamin). Instead, stick with dietary folate and use alternative forms of B12, such as adenosyl and hydroxocobalamin.

Read all about COMT and supplement interactions and learn how to check your COMT genotype to see if it is fast or slow.

Creatine and MTHFR:
Creating creatine in the body consumes about 40% of the methyl groups created in the methylation cycle.[ref] Creatine supplementation has been shown in trials to decrease homocysteine levels.[ref] This may be an especially good option for people who have slow COMT and negative reactions to methyl donor supplements.

Related article: Creatine and your genes

Riboflavin (vitamin B2):
The MTHFR C677T variant decreases its ability to bind to FAD, a riboflavin-dependent enzyme.[ref] If you have high homocysteine (a marker for heart disease risk), studies show that adding riboflavin lowers homocysteine levels in those with the A/A genotype.[ref][ref] Other research points to riboflavin decreasing homocysteine levels only if vitamin B6 levels are adequate.[ref]

Related article: Riboflavin

Choline:
Again, choline in the form of betaine can be directly used for methyl groups in the methylation cycle.[ref][ref] Betaine (also called TMG) is available as a supplement. (People with two copies of the slow COMT variant may want to be careful with supplementing with TMG.)

B-Complex:
A B-complex that contains methylfolate, riboflavin, B12, and B6 may cover all your needs. Again, keep in mind the interaction with slow COMT.  If you have slow COMT (see above), you could look for hydroxyB12 or adenosylB12, along with either very low-dose methylfolate, a low-dose of folinic acid, or simply focus on increasing your dietary folate.


Digging deeper: More than just C677T and A1298C

While the C677T and A1298C are the most well-studied variants, there are several other genetic variants in the MTHFR gene that either increase or decrease the enzyme’s function.

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Related Articles and Topics:

Histamine Intolerance, MTHFR, and the Methylation Cycle

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.