All About MTHFR Gene Variants

MTHFR is the most talked-about gene among health enthusiasts and functional medicine practitioners. It’s also the best-studied gene in nutrigenetics, the science of how genes affect nutritional status.

Short for methylenetetrahydrofolate reductase, MTHFR influences folate levels and methylation in your body. MTHFR became such a popular topic after large-scale studies linked poor methylation with chronic health problems.

However, many claims about the impact of MTHFR are inflated. People have pinned virtually every problem on MTHFR, leading to a widespread misunderstanding of this gene.

In this article, we cover the main SNPs in the MTHFR gene: rs1801133 and rs1801131. You will get to understand how your MTHFR genotype can affect your health, and what you can do to lower your risk of chronic diseases and nutrient deficiencies.

You may be surprised to hear that you might be better off avoiding methylation supplements even if you have the “bad” MTHFR variants. These variants don’t always translate to high homocysteine and health problems.

For this reason, we recommend specific lab tests for you in this report. Your labs can reveal how well your body is handling methylation, giving you a more realistic picture of the impact of your genes and lifestyle on your health. Additionally, other genetic variants and environmental factors can affect your methylation and overall health.

Methylation cycle:

• Produces the active form of folate (methylfolate)
• Converts toxic homocysteine to methionine
• Helps turn on the right genes at the right time (epigenetics)
• Produces DNA and RNA building blocks, which are necessary for cell growth and healing
• Destroys used neurotransmitters
• Generates SAM-e, which is used to methylate DNA, proteins, hormones, and neurotransmitters
• Regenerates tetrahydrobiopterin (BH4), which helps enzymes produce neurotransmitters and nitric oxide
• Helps produce glutathione, a potent antioxidant

Therefore, it is important for many aspects of health, including brain and heart health, emotional balance, detoxification, reproductive health, and cancer prevention.

Methylation (to add a methyl group) is when a methyl group is transferred from a methyl donor compound to another compound called the methyl acceptor. Methylation is important for amino acid and hormone metabolism, detoxification, and epigenetics (adjusting gene function according to the environment).

Note: In the clinical studies we’ve evaluated, MTHFR mutations are usually only a problem when homocysteine levels are high or folate levels are low.

A “SNP” refers to a single nucleotide variant at a location in the human genome. In fact, there are around 500 different SNPs that are either located inside the MTHFR gene or affect its function! However, two of the most common MTHFR SNPs are rs1801133 and rs1801131.

rs1801133 changes C (cytosine) to T (thymidine) at the message (mRNA) position 677. For this SNP, C is the normal (wildtype) version, whereas T reduces the function of MTHFR [R, R]. T at this position substitutes the amino acid 222 of the MTHFR enzyme from alanine to valine. This SNP may also be interchangeably referred to as C677T or A222V.

rs1801131 changes A (adenosine) to C (cytosine) at the message (mRNA) position 1298. For this SNP, A is the normal (wildtype) version, whereas C may slightly reduce MTHFR function. C at this position substitutes the amino acid 429 of the MTHFR enzyme from glutamate to alanine. This SNP may also be interchangeably referred to as A1298C or G429A.

• The MTHFR gene codes for the MTHFR enzyme
• Low MTHFR enzyme activity may reduce methylation and increase homocysteine

The MTHFR gene codes for the MTHFR enzyme, which is short for methylenetetrahydrofolate reductase.

The MTHFR enzyme is best known for creating methylfolate, the most active form of folate that can travel through the bloodstream and be used by cells. In the process, MTHFR helps eliminate homocysteine, a toxic amino acid [R, R, R].

The whole methylation cycle depends on MTHFR, which is why it is called a “rate-limiting enzyme”. Low MTHFR activity can make methylation as a whole much less productive [R].

Most of the negative effects of low MTHFR are blamed on increased levels of homocysteine.

Homocysteine buildup can reduce the rate at which your cell divide, which slows healing and accelerates aging. High homocysteine also worsens inflammation and increases oxidative stress. Altogether, it makes chronic health problems, including heart disease, much more likely [R, R].

If your MTHFR enzyme is less active due to genetic mutations, your homocysteine levels may rise. However, MTHFR mutations alone do not always reduce methylation and increase homocysteine.

MTHFR Supports Brain Health

In this part, we’ll zoom in on the effects of MTHFR on the brain.

Snapshot

• MTHFR protects the brain by lowering homocysteine levels
• Methylation improves mental health by keeping neurotransmitter levels in balance
• Folate enhances learning and helps create new neurons in the developing brain

MTHFR Protects Your Brain by Lowering Homocysteine

If MTHFR is not working as well as it should, homocysteine can build up. High homocysteine may lower mood, impair cognition, and provoke anxiety [R, R].

Too much homocysteine can damage neurons and glial cells that protect neurons. This makes the brain more vulnerable to any type of damage and increases the risk of Alzheimer's and Parkinson's disease [R].

Additionally, homocysteine may lower GABA in the brain. GABA is the main inhibitory neurotransmitter, which means that it works as the mind’s brakes. GABA helps you relax by countering the main excitatory neurotransmitter, glutamate. Homocysteine increases glutamate activity (via NMDA receptors), which may trigger anxiety [R].

Homocysteine can also damage the mitochondria, increase oxidative stress, and cause a leaky blood-brain barrier. A leaky blood-brain barrier lets toxins and inflammatory compounds sneak into the brain, which contributes to brain fog in some people [R, R, R].

MTHFR Boosts Mental Health by Balancing Neurotransmitters

In the brain, methylation activates the enzyme catecholamine methyltransferase (COMT) with SAMe. In turn, COMT breaks down used dopamine, epinephrine, and norepinephrine, which rise when you are under stress.

COMT helps you recover from stress and keeps your dopamine balanced. Too much dopamine can lead to aggression, psychosis, and low emotional intelligence [R, R, R].

Methylation also maintains good mood, memory, and emotional balance by creating the active form of folate. Poor MTHFR function increases the risk of cognitive and mental health problems [R].

Folate deficiency — either due to MTHFR mutations or poor nutrition — may underlie many mental illnesses, including schizophrenia, depression, autism, and bipolar disorder. About one-third of people with depression are deficient in folate [R].

MTHFR Improves Learning

Folate and its metabolites give birth to new brain cells, which supports brain development in children and learning in adults.

MTHFR Improves Fertility & Sexual Health

Snapshot

• MTHFR helps balance sex hormones
• Methylation protects your genetic material, increasing fertility in both men and women
• Folate supports ovulation in women, and healthy sperm production in men
• During pregnancy, folate prevents health complications and birth defects
• Folate eases the transition to menopause and helps keep bones strong

Low folate levels reduce fertility and increase the risk of miscarriages and birth defects [R, R].

You process dietary folate in a couple of steps. The last step is controlled by MTHFR and is important for fertility in both men and women [R].

In this step, MTHFR creates methylfolate from a compound called 5,10-methylene THF. The same compound can also be turned into DNA and RNA building blocks, which protect your genetic material. If your DNA becomes damaged and it isn’t quickly repaired, you will be less likely to pass on your genetic material — leading to infertility [R].

Therefore, you need mixed forms of folate — not just methylfolate — to give your body the precursors it needs to be fertile [R].

Poor methylation can also lead to homocysteine buildup, low SAMe, inflammation, and oxidative stress. This further lowers fertility and reduces the chance of conception and a successful, healthy pregnancy [R, R].

Women’s Health & Fertility Before Menopause

By enabling cells to divide and grow, methylation helps create healthy egg follicles and uterine lining over the course of the menstrual cycle.

Women are born with ovaries that contain all the immature eggs they will use during their entire lifespan. In healthy women of reproductive age, one (or two) follicles are selected each month to mature. During ovulation, an egg is released from the follicle.

Low methylation can increase homocysteine, which interferes with egg ripening and ovulation. In one study, women who didn’t ovulate had higher homocysteine levels [R].

Poor methylation may also lower hormones important for fertility, such progesterone.

Progesterone plays a large role during the luteal phase–the last 14 days of your cycle. It allows for embryo implantation, which is when the fertilized egg burrows itself into the uterine lining, starting off pregnancy [R].

Folate deficiency might underlie low progesterone in some women who don’t ovulate and have trouble becoming pregnant. On the other hand, women with high blood folate have higher luteal phase progesterone and are more fertile [R].

Estrogen is just as important: it helps grow your uterine lining. Your uterine lining needs to be thick and profuse to provide enough blood and nutrients to the future embryo. If your estrogen is low, your uterine lining can become thin. In turn, the fertilized egg might never implant after conception.

Among women undergoing fertility treatments, those with “bad” MTHFR variants (C677T mutation) produced less estrogen. They were also less likely to ovulate, since their response to hormones that trigger ovulation–such as follicle-stimulating hormone (FSH)–was blunted [R, R].

During pregnancy

During pregnancy, women require more folate to grow the fetus and placenta. But pregnant women absorb less and excrete more folate, which makes deficiency likely [R].

Poor methylation, low blood folate, and high homocysteine also increase the risk of miscarriages, pregnancy complications, and neural tube defects. Women with higher homocysteine are also more likely to give birth to babies with low birth weight [R, R, R, R].

During menopause

Menopause is when women stop ovulating and estrogen levels rapidly decline. Maintaining healthy folate levels, methylation, and hormonal balance early on in menopause is important for preventing health complications years down the line.

Estrogen reduces homocysteine and acts as an antioxidant. It also opposes the harmful effects of amino acids like cysteine.

Postmenopausal women normally have higher homocysteine and lack estrogen protection, which altogether makes them likely to experience health problems [R, R, R, R].

Folate also helps maintain strong bones when estrogen is in decline. Menopausal women with folate deficiency have lower bone mineral density [R, R]. In addition, folic acid may help reduce hot flashes in some menopausal women [R].

Men’s Health and Fertility

Proper methylation and normal homocysteine and folate levels help men produce healthy sperm. Keeping homocysteine low enough also improves blood flow, which prevents erectile dysfunction [R].

Men who carry the “bad” MTHFR variants (T at position 677) are more likely to be infertile. Homocysteine and low folate are likely the culprits [R].

High homocysteine worsens worsens heart health, inflames and damages blood vessels, and reduces blood flow (by lowering nitric oxide). This creates ground for erection problems and erectile dysfunction [R, R].

Men also need enough folate to produce healthy sperm. Semen is high in folate (the non-methyl form). As folate in semen increases, the fluid becomes more dense and higher in spermatozoids–in one word, fertile [R].

Poor methylation due to MTHFR mutations may also prevent sperm production. Male mice without MTHFR produce unhealthy sperm and become infertile [R, R].

Subfertile men often have low sperm density and they take a longer time to conceive. A combination of zinc and folate may help in some cases, as zinc improves folate absorption. In one study, folic acid and zinc increased sperm density by 74% — but only in men with the normal MTHFR C677 genotype [R].

This makes sense since men with low MTHFR activity couldn’t convert enough folic acid into active methylfolate. Supplementing with mixed forms of natural folate might be a better idea, though studies are lacking to confirm it [R].

MTHFR Prevents Anemia

Snapshot

• Folate helps produce red blood cells
• Folate deficiency can cause a type of anemia called megaloblastic anemia

Folate and vitamin B12 help red blood cells divide and stay healthy. Deficiency in either one causes megaloblastic anemia — a type of anemia in which red blood cells don’t properly form.  As a result, the body produces fewer red blood cells that become enlarged [R].

Fewer red blood cells can’t deliver as much oxygen as the body needs, which can lead to fatigue and weakness [R].

MTHFR Reduces Inflammation & Autoimmune Diseases

Snapshot

• Healthy methylation reduces inflammation and autoimmunity
• Folate prevents allergies and “leaky gut”

Poor methylation may underlie autoimmune diseases. It also increases homocysteine, which worsens chronic inflammation and oxidative stress [R, R, R].

Heart Health

At high levels, homocysteine in the blood sticks to healthy cells, creating harmful proteins (homocysteine-thiolactone and N-homocysteinylated proteins). These abnormal proteins may harden the arteries and cause heart disease. They can also trigger an autoimmune inflammatory response since the immune system sees them as a threat  [R, R, R].

Immune Balance

Proper methylation and getting enough folate keep your regulatory T cells (“Tregs”) in the normal range, balancing your immune system. Tregs are good: they manage the immune system, preventing autoimmunity (Th1/Th17 dominance) and allergies (Th2 dominance) [R, R].R].

If you have autoimmune or inflammatory problems, there’s a good chance that you’re deficient in Tregs–and low folate may be part of the problem. Homocysteine and low folate promote chronic inflammation and autoimmunity (by reducing Tregs and increasing Th17 cells). Folate reduced inflammation in immune cells exposed to high homocysteine [R, R, R].

Getting enough dietary folate and foods that support methylation may help. In one study, asthmatic children following a methylation-supportive diet–high in methyl donors like folate and selenium–had fewer symptoms [R, R, R].

Good methylation and adequate folate intake strengthen and regenerate the gut barrier. Folate deficiency and poor methylation can compromise this barrier and lead to a leaky gut. In turn, harmful substances that trigger autoimmunity and chronic inflammation enter the bloodstream [R, R, R].

If you struggle with autoimmunity, allergies, or chronic inflammation, make sure your folate and homocysteine are within the optimal range (see the Lab Test Analyzer).

MTHFR and Histamine

The relationship between methylation and histamine is complex.

On the upside, methylation activates one of the enzymes that break down histamine (histamine N-methyltransferase or HNMT) using SAM-e. It also helps flush histamine from the body [R].

However, the downside is that methylation increases histamine release from mast cells [R].

All in all, the effect of methylation on histamine is unpredictable.

Dangers of Folate Deficiency and Low Methylation

Before cancer develops, many tumor-like cells have to be created. These cells are inflammatory, have unstable genetic material, and can evade the immune system [R].

Healthy methylation and folate levels protect the DNA. Folate deficiency and poor methylation lift this protection, giving cancer cells an opportunity to form.

In the last step of the methylation cycle, a compound called methylene-THF is used to create either the active form of folate or DNA building blocks–nucleotides. Lacking dietary folate, your body can’t create this compound or nucleotides. This can make the DNA more vulnerable to cancer-promoting mistakes in its code [R, R].

Methylation can also silence or “turn off” cancer-promoting genes. Poor methylation lowers SAM-e and has the opposite effect: it turns off cancer-fighting genes and turns on cancer-promoting genes [R, R].

Additionally, low MTHFR increases homocysteine, which promotes inflammation and oxidative stress–both of which can contribute to cancer [R].

There are several forms of folate (vitamin B9) supplements on the market that are chemically distinct. 

The term “folate” refers to a group of substances that all function as vitamin B9. In addition, you may come across trademarked folate supplements, such as Metafolin and Quatrefolic, which are both supplemental forms of methylfolate. 

This section will help you understand the differences and choose the best form of folate supplements for you.

Folate is an inclusive term for a family of compounds that include all the different forms of vitamin B9, including [R]:

• Folic acid
• 5-methyltetrahydrofolate (5-MTHF) – the same thing as [6S]-5-MTHF, and methylfolate , 5-methyltetrahydrofolate, 5-methyl THF, and 5-MTHF
• 5-formyltetrahydrofolate (5-FTHF) or folinic acid
• 10-formyl-tetrahydrofolate (10-formyl-THF)
• 5,10-methylene-THF (5,10 methylene-THF)
• tetrahydrofolate (THF)
• dihydrofolate (DHF)

Natural dietary folate includes all of the above, except folic acid. In unfortified fruits, vegetables, meat, and legumes, most folate is in 5-MTHF and folinic acid forms [R, R]. Natural folate is much less stable than folic acid, so it can lose activity over days or weeks. 

In addition, natural folate comes with a long chain of glutamate residues. The whole chain has to be cut off, leaving only one glutamate before folate can be absorbed [R]. The enzymes that cut off this chain of glutamate require zinc to function correctly [R]. Plus, gut acidity is important for the absorption of folate, so people with low stomach acid may have a hard time absorbing natural folate [R]. 

Folic Acid typically refers to an oxidized synthetic and water-soluble form of folate that typically does not exist in nature. Because folic acid is very stable, lasting months or years, it is most commonly used for fortifying foods, such as flour and grain products [R]. 

Synthetic folic is also called pteroylmonoglutamic acid because it’s made by joining pteroic acid with the amino acid glutamate. Although folic acid is readily absorbed thanks to its single glutamate residue, it is not active as a coenzyme: the enzyme dihydrofolate reductase (DHFR) needs to convert it to tetrahydrofolate for further use [R, R]. 

MetafolinⓇ is the calcium salt of methylfolate [R]. The complex with calcium ions allows methylfolate to be in crystalline form, which is much more shelf-stable than natural methylfolate. In addition, it is absorbed as well as folic acid in the gut [R]. Metafolin bypasses the requirement for DHFR and MTHFR.

QuatrefolicⓇ is the glucosamine salt of methylfolate. It is shelf-stable and 100 times more water soluble than Metafolin. It is absorbed in the intestine and therefore does not require stomach acid [R, R, R]. Therefore, it is much better absorbed than folic acid and methylfolate [R]. Quatrefolic may be more effective and beneficial for people with gut or malabsorption problems.
Folinic acid is the form that crosses the blood-brain barrier more easily than other forms [R].