~ The MTHFR gene impacts how your body utilizes folate (vitamin B9) for creating neurotransmitters, detoxifying toxicants, and maintaining a healthy heart.
~ Genetic variants can impact how well this gene works.
~ Optimizing diet and supplements related to methylation may impact several aspects of wellness.
Check your raw data for MTHFR C677T, A1298C, and more
This article shows you what to check in your raw data, then explains the scientific research on the MTHFR variants. At the end of the article, you will find solid, evidence-based lifestyle solutions for optimizing the MTHFR variants.
Frankly, there is a lot of misinformation on the internet about the MTHFR gene mutations, so I will explain the peer-reviewed research studies here.
I’ll clearly explain how to optimize your diet (or add in supplements) if you carry MTHFR genetic variants.
MTHFR Gene Mutations Genotype Report:
Let’s put the rest of this article into context by checking your two more common MTHFR polymorphisms first. (I’ll include other MTHFR variants later in the article).
Tests for MTHFR:
You don’t need to do specific genetic testing or buy health reports for the MTHFR variants. The information is already included in your raw data from 23 and Me, AncestryDNA, MyHeritage, and more.
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%
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 —.
Let’s dig into the details of what “MTHFR” is…
What is the MTHFR gene?
The MTHFR gene codes for an enzyme called methylenetetrahydrofolate reductase.
There is a lot of swirl about MTHFR — with people thinking the “MTHFR mutation” is the cause of everything under the sun. The swirl seems to have caused a backlash, with doctors claiming the SNPs are completely unimportant.
I’m going to cut through the hype and explain the research:
- Research shows that the MTHFR variants statistically increase the relative risk of quite a few health issues…
- However, you have to take into account your diet and your exposure to environmental factors such as toxins.
- For some, the MTHFR variants will have little to no impact.
What is the methylation cycle?
The MTHFR gene encodes an enzyme that is a key part of the methylation cycle.
Methylation is the adding and removing of a methyl group (CH3) to amino acids, DNA, and other enzymes or proteins.
Forming new molecules:
Most of the molecules in our body are chains of hydrocarbons — carbons plus hydrogens. So adding a methyl group stacks on one more link in a hydrocarbon chain.
The methyl group then changes the original molecule into something different.
Let’s take melatonin as an example: A methyl group is added to serotonin to convert it to melatonin in a two step process.
A methyl group is also vital for your DNA in the cell nucleus. By binding to specific spots on a chromosome, methylation can turn on and off genes as well as maintain and repair your DNA.
Detoxification and breaking down substances:
Methylation is essential in the nervous system, in the production and breakdown of neurotransmitters, and in detoxifying some environmental toxicants.
The methylation cycle also intimately impacts heart health. It 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 have been linked to high homocysteine levels and heart disease in many studies.
High homocysteine is also linked to increased blood clots.[ref]
Additionally, the 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
As you can see, optimizing your methylation cycle can balance many health issues.
So how does the body make methyl groups? That is where MTHFR comes in.
What does the MTHFR enzyme do?
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 in the coding of this gene affect more than half the population.
Specifically, the MTHFR gene codes for an enzyme called methylenetetrahydrofolate reductase that turns folate into the active form, 5-methyltetrahydrofolate, that your body uses.
This enzyme, along with the active form of vitamin B-12 (methylcobalamin), drives an essential portion of the methylation cycle. While folate is important, I’ll also explain in the Lifehacks section how choline can also be a source of methyl groups…
Symptoms of MTHFR: Effects from the SNPs
If you do a search on the internet for MTHFR, you’ll find articles explaining the ‘symptoms of MTHFR’. You’ll see lists of symptoms like ADHD, autism, chronic fatigue, cardiovascular disease, hormone issues, stork bite, tongue tie, and more will pop up.
These aren’t really symptoms of MTHFR… The MTHFR gene is essential, important in development and cells being able to function. You can’t live without the gene!
The list of symptoms that you’ll see are simply things that are statistically associated with the gene variants, but all of these ‘symptoms’ are health conditions that have multiple causes.
The MTHFR variants can contribute to the risk of diseases such as autism, heart disease, and depression; however, the variants are not the sole cause of the disease.
What do C677T and A1298C mean? Getting the terms right…
Let’s talk about terminology…
- A mutation is a change in a gene that happens in less than 1% of the population. These are rare changes.
- A polymorphism is a change that occurs in the gene for more than 1% of the population. We all have lots of different polymorphisms — these are the small changes that make us all unique.
The MTHFR C677T variant is considered a single nucleotide polymorphism – a SNP. One nucleotide base pair (the As, Cs, Gs, and Ts) is different for part of the population.
By genetic definitions, MTHFR C677T and A1298C are NOT mutations. Both are common variants, or SNPs. And both polymorphisms are found in about half the population.
Heterozygous means one copy of the polymorphism, and homozygous means two copies.
Conditions linked to the MTHFR C677T or A1298C variants
While these variants are common, they do impact health and wellness — especially for people who don’t eat a lot of foods high in folates, such as dark leafy greens or beef liver.
The MTHFR gene is one of the most well-researched genes, with over 6,000 studies investigating the common C677T variant.
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]
- preeclampsia and hypertension in pregnancy[ref][ref]
- depression or anxiety[ref][ref][ref][ref][ref]
- problems after nitrous oxide – uncommon[ref]
Important to understand: Carrying 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 diseases when diet and lifestyle factors are not optimal.
Importantly, food choices or supplemental methylfolate can eliminate the problems from the MTHFR variants.
Depression and the MTHFR Gene Variants:
Let me go a little more in-depth here on the research that shows that MTHFR variants increase susceptibility to mood disorders.
- A meta-analysis, which included 26 different published studies, found that the MTHFR C677T variant was associated with an increased risk of depression in people with different ancestry groups.[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. The study population group was Polish women.[ref]
- Women who were homozygous (two copies) for 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]
I do want to point out that not all studies agree, and some researchers found that the MTHFR C677T variant has little to no impact on depression risk. The difference may be due to the role that diet plays here. People who eat a diet that includes more folate (green veggies, legumes, etc.) may not be at an increased risk of mood disorders, while people who are folate-deficient may be more susceptible to depression.[ref][ref]
Related article: Getting to the root cause of depression
Pregnancy and MTHFR:
One of the first research links with MTHFR 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.
This is a big topic and I have an in-depth article on it:
Related article: MTHFR, pregnancy, and infertility
Getting specific on the MTHFR C677T variant:
The C677T SNP is a change in one nucleotide base at one spot in the gene. The variant slightly changes the protein structure, which causes the enzyme to break down faster at normal body temperature (thermolible). Faster enzyme breakdown reduces the amount of enzyme available.[ref][ref][ref]
People with the rs1801133 A/A genotype have the greatest impact. They have about a 70% reduction in enzyme function.
Combined with a diet lower in folate, this more severe reduction in enzyme function impacts many aspects of health.
For example, recent research studies show:
- In cancer patients treated with 5-FU, neutropenia is 7-fold more likely with C677T.[ref]
- In epileptic patients, supplemental folate and B12 decreased seizure frequency in C677T carriers.[ref]
- In women with two copies of C677T (AA genotype), average blood pressure was higher by 10 mmHg for systolic BP.[ref]
- The C677T variant increases the relative risk of autism a little (33-66%). Keep in mind that this is an increase in relative risk, and other environmental and genetic factors are also involved in autism.[ref]
Why does the MTHFR variant increase the risk of heart disease?
Extensive studies are showing a link between MTHFR C677T and an increased risk of cardiovascular disease.
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] With heart disease being the number one killer, a 38% increase in relative risk is important.
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] High homocysteine levels have long been a marker of increased risk of heart disease. According to the Journal of the American Heart Association, elevated homocysteine “may be due to inherited mutations in the MTHFR gene; such mutations are very common.”
It is more than just high homocysteine, though.
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.[ref]
The endothelium is the lining of blood vessels, and endothelial function controls how the blood vessels relax or contract to control blood pressure. Additionally, endothelium function involves the release of the right enzymes to control blood clotting, immune function, and platelet stickiness. The study showed, using a mouse model of MTHFR C67T, that SIRT1 was down-regulated even when homocysteine was normalized. This affected clotting and endothelial function, and supplemental resveratrol helped to restore endothelial function.[ref]
Overall, optimizing your methylation cycle can be important to heart health. Take the knowledge of carrying a C677T variant as a ‘heads up’ to pay attention to your heart and be proactive about your health.
Related article: MTHFR, riboflavin, and reducing high blood pressure
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]
Looking at the data:
- Meta-analyses showed that the MTHFR C677T variant increased the risk of migraines with aura for all populations. In non-Caucasians, the increased risk was a whopping 3-fold.[ref][ref]
- A study examining the electrophysiological characteristics of migraines found that carriers of the MTHFR C677T variant were more likely to get migraines and more likely to have photophobia with migraines.[ref]
- The A1298C variant was associated with the risk of migraines in a North Indian population.[ref]
Related article: Getting to the root genetic cause of migraines
Detoxification and MTHFR: heavy metals and more
Another way methyl groups are necessary to health is by detoxifying toxicants. The body has many different means of rendering toxicants water-soluble and able to be excreted. Some of these involve the addition of methyl groups.
For example, 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 C677T
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.
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.
Studies finding protective effects:
- 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]
- Having either one or two copies of MTHFR C677T is protective against susceptibility to retinoblastoma[ref] and oral squamous cell cancer.[ref]
- A longevity study in China found that the T allele was more prevalent among their long-lived group (aged 90 and older), especially in females.[ref]
- Another Chinese study found two copies of the C677T variant (AA genotype) were protective against gastric cancer.[ref]
Why does decreasing methyl groups protect against cancers in the colon or stomach? The methyl groups are needed to support the excessive and quick growth of tumors, so limiting them decreases the replication of cells, including cancer cells. In fact, methotrexate was one of the first chemotherapy drugs discovered. Methotrexate is an ‘antifolate’ that works by inhibiting the conversion of dietary folate into methylfolate. The lack of methylfolate then inhibits the excessive cellular growth of tumors.[ref]
Studies finding protective effects of MTHFR A1298C:
The MTHFR A1298C variant (GG or GT) is associated with a decreased risk of hypothyroidism.[ref]
Why do some doctors think that MTHFR variants are not important?
Extensive research on MTHFR, one of the most studied genes, has shown that MTHFR variants are linked to an increased relative risk for the disorders listed above and many other diseases.
While an MTHFR variant increases susceptibility to many chronic diseases, it is not the absolute cause of most diseases. Instead, it’s just one part of the picture.
When patients flood into the doctor’s office to demand treatment for ”having the MTHFR gene”, the automatic backlash is to say that MTHFR variants aren’t important. (Terminology pet peeve – everyone has the MTHFR gene! It’s one of those genes you literally can’t live without.)
Instead, talk with your doctor about how diet and lifestyle impact risk for diseases. Also, talk with your health care provider about supplements you are taking.
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.
Hey! Want to go further with your genetic raw data? Join as a Member!
Additional MTHFR Genotype Report:
There is more to MTHFR than just C677T….
Additional variants to check for that decrease MTHFR enzyme function:
Check your genetic data for rs2274976 G1793A or R594Q (23andMe v4, v5; AncestryDNA):
- T/T: associated with cleft lip[ref], neural tube defect[ref], higher homocysteine, and folate deficiency[ref], increased risk of schizophrenia in children[ref][ref], cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref], risk of lower bone mineral density if B12 is also low[ref]
- C/T: somewhat increased risk of schizophrenia, cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref]
- C/C: typical
Members: Your genotype for rs2274976 is —.
Variants that are associated with positive outcomes:
Check your genetic data for rs9651118 (23andMe v4; AncestryDNA):
- T/T: most common genotype
- C/T: decreased risk of liver cancer[ref], slower cognitive decline in the elderly[ref], lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]
- C/C: decreased risk of lung cancer[ref], lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]
Members: Your genotype for rs9651118 is —.
Check your genetic data for rs13306560 (23andMe v4; AncestryDNA):
- T/T: avg 5.2 mmHg lower diastolic blood pressure[ref], protective against Parkinson’s[ref]
- C/T: avg 2.6 mmHg lower diastolic blood pressure
- C/C: typical
Members: Your genotype for rs13306560 is —.
Check your genetic data for rs17367504 (23andMe v4, v5; AncestryDNA):
- G/G: protective against hypertension, preeclampsia[ref]
- A/G: protective against hypertension, preeclampsia
- A/A: typical
Members: Your genotype for rs17367504 is —.
Lifehacks: Actions you can take with MTHFR
Knowing that you carry an MTHFR genetic variant can help guide your choice of foods and supplements. By optimizing your diet, you can mitigate the risks from the MTHFR variants.[ref]
Diet for MTHFR:
Increase folate-rich foods:
Increasing your intake of folate (vitamin B9) from foods will help mitigate some of the risks from the MTHFR variant. Foods containing lots of folates include leafy greens, lentils, liver, asparagus, liver, and broccoli.
Is dietary folate enough?
A recent study showed that increasing folate-rich foods reduced homocysteine levels and inflammatory markers in women with the MTHFR C677T variant. The study showed that eating 191 mcgs of folate from vegetables each day caused a significant beneficial change.[ref]
Need recipe ideas? Check out Folate-rich foods and recipes for MTHFR
Folate is not exactly folic acid…
Note that when looking at folate content, you need to ensure the ingredients list doesn’t refer to folic acid (a synthetic form found in processed foods). Not everyone processes folic acid the same way.
Related article: Folic acid and your DHFR gene
Increase your 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 metabolite of choline, betaine, is what works through the methylation cycle; therefore, food sources of betaine (beets, quinoa, and spinach) are also helpful here. Supplemental betaine (also called TMG) is also available. (People with two copies of the slow COMT variant may want to be careful with supplementing with TMG.)
Related article: Choline-rich foods and recipe ideas
If your diet doesn’t provide enough nutrients needed in the methylation cycle, you may want to consider supplements to increase your intake. Alternatively, you could experiment with using supplements on a short-term basis to see exactly which nutrients you need to include more of in your diet.
Supplemental methylfolate and B12:
- If you aren’t getting enough folate from foods, you could try a low-dose methylfolate supplement. Methylfolate is the active form of folate (vitamin B9). Keep in mind the RDA for folate is 400 mcg.
- Vitamin B12 is also important in the methylation cycle, so you need to ensure you are getting enough B12 either through diet (animal-based foods) or supplements.
Side effects with methylfolate:
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 methylB12. 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 to see if it is fast or slow.
Read the labels on supplements that you buy. Many methylfolate supplements provide a lot higher dose than the 400 mcg RDA (or 800 mcg in prenatal vitamins). In addition to side effects, you may want to be cautious with higher doses due to folate being needed for cancer growth.[ref]
Talk with your doctor if you have any questions about supplements.
The rest of this article goes into details on supplements and other genetic variants to consider along with MTHFR. It is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.
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Vitamin B12 genes
MTR (methionine synthase) and MTRR (methionine synthase reductase) are two genes involved in the conversion of homocysteine to methionine, and a couple of fairly common gene variants cause the genes to work differently.
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Ganz, A. B., Shields, K., Fomin, V. G., Lopez, Y. S., Mohan, S., Lovesky, J., Chuang, J. C., Ganti, A., Carrier, B., Yan, J., Taeswuan, S., Cohen, V. V., Swersky, C. C., Stover, J. A., Vitiello, G. A., Malysheva, O. V., Mudrak, E., & Caudill, M. A. (2016). Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. The FASEB Journal, 30(10), 3321–3333. https://doi.org/10.1096/fj.201500138RR
García-Minguillán, C. J., Fernandez-Ballart, J. D., Ceruelo, S., Ríos, L., Bueno, O., Berrocal-Zaragoza, M. I., Molloy, A. M., Ueland, P. M., Meyer, K., & Murphy, M. M. (2014). Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (Mthfr) and methionine synthase reductase (Mtrr) polymorphisms on homocysteine. Genes & Nutrition, 9(6), 435. https://doi.org/10.1007/s12263-014-0435-1
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