Our Take On The MTHFR Gene

Editor’s note: Soon after we put up this post, the US Preventive Services Task Force released updated guidelines for folic acid supplementation that include specific mention of MTHFR.

The methylenetetrahydrofolate reductase gene, more commonly known as MTHFR, is the most asked-about gene by 23andMe customers. mthfr-image_blog1x1 Some websites and products have made bold claims that common genetic variants in MTHFR can cause a wide array of health conditions, ranging from blood clots and cancer to autism and migraines.

So we decided to dig deeper into the published scientific literature to evaluate the evidence. Our conclusion? Despite lots of research — and lots of buzz — the existing scientific data doesn’t support the vast majority of claims that common MTHFR variants impact human health.

The biology
Here’s what we know about MTHFR.

The MTHFR gene contains instructions for making an enzyme that’s important for metabolizing folate (also called folic acid or vitamin B9). MTHFR also helps our cells recycle homocysteine, a chemical in the blood, into methionine, a building block for proteins.[1]

We also know that there are two common naturally occurring variants in the MTHFR gene, called C677T and A1298C. When the MTHFR gene has either of these two variants, the resulting MTHFR enzyme is slightly less active, and this can lead to decreased levels of folate and increased levels of homocysteine in the blood.[1]

The hype
Some websites have spread the idea that having one or two copies of an MTHFR variant can lead to dozens of negative health consequences. There are a couple problems with this claim. First, it’s unlikely that variants in a single gene could cause dozens of unrelated health problems. Second, the C677T and A1289C variants are very common: in some ethnicities, more than 50 percent of people have at least one copy of one of these variants. Most disease-causing genetic variants are not this common.*

Another claim about MTHFR is that people who carry an MTHFR variant should avoid foods that are fortified with folic acid. However, there’s no evidence that individuals with an MTHFR variant should reduce their folic acid intake.

The scientific evidence

Good sources for information on health and science
Websites and blogs are filled with misinformation about MTHFR. When you’re looking for information about science and health, make sure you find trustworthy sources. Here are a few of our favorite sites for information about genetics, health, and disease:• Genetics Home Reference https://ghr.nlm.nih.gov/
• GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1116/)
• Mayo Clinic (http://www.mayoclinic.org/patient-care-and-health-information)
• Centers for Disease Control (http://www.cdc.gov/)
• US National Library of Medicine (https://www.nlm.nih.gov/medlineplus/)
• Disease-specific sites, like the National Cancer Institute (http://www.cancer.gov/), the American Heart Association (http://www.americanheart.org/), and the American Diabetes Association (http://www.diabetes.org/)
• Understanding Health Research (http://www.understandinghealthresearch.org/), a tool to help evaluate the quality of health studies.

Over the past two decades, scientists have examined associations between the MTHFR C677T and A1298C variants and more than 600 medical conditions.[2] Despite thousands of scientific publications, the evidence linking MTHFR to most of these health conditions is inconclusive or conflicting. For example, some studies report an increased risk of heart disease for individuals with two copies of the C677T variant,[3] while other studies report no association with heart disease.[4] The same is true for cancer,[5][6] blood clots,[7][8] and many other well studied health conditions.[1][9][10]

There is one exception: women with two copies of the C677T variant appear to have slightly increased risk of having a child with a neural tube defect like spina bifida.[11][12] However, according to the National Institute of Child Health and Human Development, as well as other countries’ nationwide health programs, folic acid supplementation reduces the risk of neural tube defects in all pregnant women, including women with an MTHFR variant.[13]

The takeaway
Based on the existing data, scientists at 23andMe have concluded that people should not interpret their genotypes at the common MTHFR variants as having an effect on their health.
In order for a connection between a genetic variant and a health condition to be considered real and clinically meaningful, well-run scientific studies need to show convincing and consistent evidence for that association. As statements from multiple scientific and medical organizations indicate,[14] [15]  that is currently not the case for the common MTHFR variants. Our team will continue to monitor research in this area — as we do for a wide variety of genetic research — and evaluate new information as it becomes available.

*Note: Some very rare variants in MTHFR can cause a severe condition called homocystinuria, which affects fewer than 1 in 200,000 people in most ethnicities.[16] These variants are different from the common variants described here and discussed throughout the 23andMe community and online.

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  • twistedgenes

    I for one do have issues with MTHFR I have been wasting away and having MS symptoms until I researched this and found that I needed to eat more organic green leafy vegetables full of folate which our bodies convert to folic acid. Taking folic acid is not on my menu. Dr Ben Lynch has excellent articles and lectures on these snips he can see MDs don’t even read the own studies on PubMed. Since I started supplementing with the right kind of B vitamins along with eating more green leafy vegetables I have gained muscle mass and stopped having MS symptoms. I do not trust the CDC at all, they are not our friends.

  • Fred Lorey

    I found the summary on MTHFR in some areas excellent and well referenced, but in other areas quite insufficient and not supported by data. I refer specifically to newborns with MtHFr who can have several serious clinical symptoms but which can be detected by Newborn Screening and treated effectively. Newborn screening was barely mentioned in the review but the intent seemed to be to discredit adults with MTHFR and the folate connection. The states of CA and MN screen for MTHFR in newborn screening because it is detectable and severe symptoms can be ameliorated with early intervention. Please see the following article http://www.jpeds.com/article/S0022-3476(10)00151-4/fulltext As a member of the HHS Secretary’s committee on hereditary disorders which does evidence based review on nominated disorders, I can say much misinformation is uncovered, even in the literature, during the process. I would like to see more information on newborn symptoms with MTHFR and less on the unproven associations with childbearing women with MTHFR, many of whom were unaware they had the disorder.

  • Leta

    You do not discuss the use of L-Methylfolate (e.g., Deplin) to augment antidepressants for people with both variants. It’d be great if you could review that literature.

  • bklyn2017

    “However…folic acid
    supplementation reduces the risk of neural tube defects in all pregnant
    women, including women with an MTHFR variant.”

    But why not take pre-methylated folate instead of folic acid, if you have 2 copies? Isn’t it better safe than sorry? I just read the article linked to in Footnote 13 and it does NOT state that folic acid supplementation lowers NTD risk in women with MTHFR variants. Could you clarify which section implies that? The article does not contain the phrase “MTHFR” or “C677T,” either, though there is some discussion of epigenetic changes and DNA methylation regarding cancer.

    • Crystal Handal

      ^ It would be wonderful to have clarification here.

  • 23blog

    Hi Kelly,
    I don’t know that I can address any of the issues you’ve brought up in your comments. I can say that our researchers have looked pretty deeply into the scientific literature and our own data. This post is meant to give their view of the state of the science on MTHFR right now.

    • Ann

      I think it would be most helpful if you could create surveys to gather information for health conditions for those with homozygous MTHFR as you have done with other genetic gene mutations and health conditions. Homozygous is not common in the population. I am 1298C
      homozygous. I am in the process of having my 23andme data analyzed by a professional so I might get help with this. It is disappointing if not irresponsible that “23andMe have concluded that people should not interpret their genotypes at the common MTHFR variants as having an effect on their health.” That is not acceptable. There is research showing the opposite albeit some from outside the US. When the traditional medical community is actively ignoring or dismissing it there will be very few well run scientific studies in the US making it is hard to empirically connect cause and effect. It is a very complex issue and most physicians do not comprehend it. In addition, it is now well documented that the Center for Disease Control has corrupt and conflicted interests in their research and practices and therefore a big credibility issue and therefore not a good source of information in my opinion.

  • Colleen Fadollone

    I have a cousin needing Bone Marrow to save his life, here is his info, Please help if you can.

    Write something…

    News Feed

    FROM NOTIFICATIONS

    Philip David Thibodeau shared a link.

    · 15 hrs · Dearborn, MI

    Hey cousins this may not be the place to post this but I need help. I’ve suffered a relapse of my AML Leukemia and now require a bone marrow transplant. Since we all share Pierre as a great etc. etc grandfather maybe theirs a chance that we could be a match some how some way. Please go to Be The Match and get a cheek swab kit just in case there’s a match out there for me or someone else.

  • Crystal Handal

    Can the news you are breaking be linked back to the genetic variant?

  • Kirk Anderson

    This is where I have an issue with researchers. Due to variations in dietary intake and other genetic factors we can all have different health outcomes related to this gene, therefore do not anticipate any concrete evidence related to this gene until researchers take diet into account.

    My son, his mother, my sister, nephew, my mother, and I have either C677T or A1298C, with some similarities and differences. The healthier the diet, the less likely there will be any impact, including asymptomatic. Also, as we age, especially in my case (almost 50), the more symptoms appear. Something to think about; if your body has to ration your nutrition due to a deficiency for long periods of time, the more impact it can have on any organ. I also believe these genes cause other deficiencies, the following supplements have dramatically improved my symptoms:

    Niacin – 200mg
    Pyridoxal Phosphate – 50mg
    Methylfolate (Jarrow) – 800mcg
    Methylcobalamin – 2500mg
    SAM-E – 400mg

  • Joey Redner

    Did you look at any studies on being homozygous for MTHFR and the use of nitrous oxide? Nitrous is very commonly administered and studies strongly suggest it has a major negative impact on people that are homozygous for MTHFR, which in my opinion has an “effect on your health” the way commonly administering folic acid might. As to folic acid reducing neural tube defects, awesome that is a good outcome for the fetus, but are the studies looking at just the baby or the long term health of the mother as well, who is also getting this mega dose of folic acid? I was literally at this site ready to order four of your tests for my daughters since I am homozygous for the C6777T variant. But your statement that “it’s unlikely that variants in a single gene could cause dozens of unrelated health problems,” is so shockingly ignorant that I can’t bring myself to send you any of my money. The MTHFR variant isn’t causing ANY health problems in and of itself, true enough. But the reduction in the efficiency of the methyl pathways is causing health problems and loads of studies show that reduced function in people who are homozygous for 1 or more of the MTHFR variants. If you dont get adequate nutrients you dont get good health. Period. It is like saying genes that result in you being very pale have nothing to do with you getting a sunburn and then pointing to the majority of the population that isn’t very pale. It is true that 1 heterozyous MTHFR mutation is common and studies do suggest there is little negative effect, but homozygous mutations are not all that common (in the 10-11% range) and many studies do show a markedly reduced function of the methyl pathways and negative reactions to common folic acid and B vitamin supplements.

    http://www.nejm.org/doi/full/10.1056/NEJMoa021867#t=article

  • Nikki Preede Kimbleton

    I just did an in-depth news story with doctors from Mayo, one of the top pediatricians in Florida… as well as several other doctors and two pharmacists… and this is not what they are saying AT ALL. I read all of the studies that you reference and actually just sent this link to them. I was about to order your test for the rest of my family— but I think I will stick with the test I used before, despite the price. As someone who just tested with the C677T mutation as part of the story I was doing… I’ve been on a methylated version of vitamins for a month and my b12 and folate levels are finally normal. They’re been seriously low for years, even with regular supplements and I have always felt like crap. With this and a diet change in the last month… because of finding out that my body is a little challenged thanks to the mutation…I feel a marked difference. I’ve talked to dozens of people since the story aired that have the same experience. I guess we are all crazy. Just surprising to me that the article is so opinionated. And I am not basing that on the references… I read them and I do accept this is not the cause for everything. BUT, it certainly is an issue and something that can give you a lot of power if you know that you have a mutation and should be following a healthier lifestyle and taking the right supplements.

    • Ben

      Totally agree. For me, the research led me to some interesting conclusions about the link between the gene mutation and anxiety/depression. But let’s be clear, J&J is a large (series C) investor in 23 and Me. If something as easy as supplements and diet could help people heal, that would put big pharma out of business. Not saying 23 and me is biased, but there are people at their table (and in their wallets) that would not benefit from these claims. I currently help anxious people heal, naturally, and the result of taking the proper supplements and changing their diet has been incredible. Long story short, test for yourself. Don’t rely on the government (the ones funding the “tests” that 23 and me said we need more of), Big Pharma (the ones benefiting by us being in the dark), or doctors to always know what you need. Doctors mean very well, but most of them (1) don’t get paid by prescribing supplements and (2) only took 1 semester of nutrition in Med school. Do your own research, and if you are healthy, start testing with the accountability of a trusted doctor.

    • Eli

      Hi Nikki,

    • Eli

      What kind of test is the one you said you used before? and do you know what is the main difference with this one MTHFR Gene? Thank you!!

    • Jelena Evans

      Nikki I’m also interested in MTHFR test that you have opted out with? Could you please advice?

    • Abigail Apple

      I could not agree more. 23andMe needs to “get with the program” and accept the overwhelming evidence that these mutations are a major threat to health for so many people. My third child was anencephalic. My next pregnancy miscarried. My oldest sister had cleft palate. If you go to the NIH page for MTHFR, these are listed as directly being caused by MTHFR. So 23andMe, what’s up with you people? I’m 64 now, I have several autoimmune disease, a long list of other ailments, and my B12, folate, and B6 were found to be dangerously low. My mother died of dementia from B12 deficiency due to the MTHFR. The doctors were baffled because her “Alzheimer’s” did not show any plaques in the brain—well, it’s because she had dementia due to severe B12 deficiency, due to MTHFR; it was not Alzheimer’s. She died of dementia and she did not need to suffer so horribly the last ten years of her life, slowly forgetting who she was and who everyone was. Remember, her first child had cleft palate. And her father dropped dead at 67 of heart disease. His mother dropped dead at 45 of heart disease. His sister had major depressive disorder and committed suicide in her late 50’s. Depression and addiction runs in my family tree. My daughter and I have both been tested (Mayo Clinic) and were found to have defects on the A1298C and the C677T. My daughter has Lupus, Fibro, Livedo Reticularis, Migraines, and Cold Urticaria. I have Lupus, Sjogren’s, MCTD, Raynaud’s, hypothyroidism, anemia, gastroparesis, dysautonomia, intestinal dysmotiliy, esopahgeal dysmotility, and a ton other stuff that is killing me. I just got my first gamma globulin infusion last week. Hoping it will help so I can get out of bed and enjoy life al little again. My husband gives me B12, B6 and B1 shots and I take folate and methylated B12 as well. Slowly, slowly, slowly, I’m getting a little better, but there is a lifetime of damage that can’t be undone.

  • Jelena Evans

    I find this article to be extremely elusive and opinionated as well. I have done some research into this question on my own as well due to my son’s mutation and diet as well as supplementation change has resolved his many issues. Now I’m not sure whether to order the test as well. As a matter of fact I have sent an email asking whether 23andme does provide info on MTHFR and the response was negative. How does this explain comments from people who have received MTHFR results from 23andme? Can anyone give definite answer at all?

    • Josh

      Jelena, you can download the raw data from 23andme and upload it to geneticgenie.org to get the MTHFR results.

      • Golden Scarab

        Same thing with Ancestry data if you opt for that test instead.

        Both tests are run on the same platform – 23andMe does include additional information vs Ancestry. But you can get the basic MTHFR information from either option.

  • Golden Scarab

    This blog is correct that MTHFR mutations are NOT the bogeyman for every conceivable disease out there. However, that seems to be an intentionally misleading strawman that they created just to discredit.

    MTHFR mutations DO cause reduced efficiency or inability to metabolize folate (folic acid). Period – this is proven and accepted science.

    The idea that a mutation(s) cannot be widespread and harmful is just intentionally misleading. “Second, the C677T and A1289C variants are very common: in some ethnicities, more than 50 percent of people have at least one copy of one of these variants. Most disease-causing genetic variants are not this common.” This statement is problematic for many reasons, but the primary one is that folic acid supplements were only mandated in enriched cereal grain products (i.e. enrich flour) in the US in 1996 and were not fully implemented until 1998. The way this article is worded, it seems as if 23andMe is trying to imply that folic acid is a naturally occurring substance that humans have always had and needed in order to survive. That is not true. Folic acid is a synthetic variant of naturally occurring methyl-folate (i.e. what is found in our foods). People with the MTHFR mutations can and do process methyl-folate perfectly well. It is only the synthetic version, folate aka folic acid, that cannot be processed when one has the MTHFR mutations.

    Folic acid was chosen as a supplement vs naturally occurring methyl-folate because of long term stability on the shelf (i.e. in food products and vitamins). So the presence of folic acid in our foods and vitamins is a man-made problem to begin with. Once we understand that it should not be surprising that this mutation could be so wide-spread and also harmful. It wasn’t until we tried to improve upon naturally occurring methyl-folate by supplementing with folic acid that the problem even existed.

    Please do not conflate this with solid scientific evidence that lack of methyl-folate in a diet can and does lead to birth defects and a host of other health problems. Additionally, in people without the MTHFR mutations, folic acid supplements can and do improve health, reduce birth defects, etc… But the need for folic acid supplements falls squarely on our diets which do not provide sufficient levels of basic, required nutrients (not just methyl-folate…)

    Also, be aware that folic acid supplements are not at worst simply just wasted or of no benefit. Instead, for people with the MTHFR mutations they can actively cause harm. Even though MTHFR individuals cannot metabolize folic acid, it does preferentially bind to and block the receptors for methyl-folate. That means that if you have folic acid in your diet and have the MTHFR mutations then you body will not metabolize methyl-folate that it may have access to from your diet or supplements.

    If you do have these mutations, eliminating folic acid as much as possible from your diet could be very beneficial. You do not have to be draconian about it – that piece of enriched pasta has not killed you yet. Folic acid is water soluble so your body does not retain it long term. So if you are in a situation where you eat enriched foods (i.e. you are invited to dinner for a friend, travelling for business, etc…) you can be gracious and eat the food. Just make it as much of an exception instead of a rule as possible.

    And do look into vitamins without folic acid. If you are searching for such vitamins, it is easier to find them if you look for vitamins WITH methyl-folate vs vitamins without folic acid. This simple change in search terms will yield drastically different results. I don’t want to be accused of posting an advertisement for any specific vitamins, but do know that there are ready available brands available at Target / Walmart / Costco / etc… that do not cost significantly more than more traditional options. Yes, you can be health conscious in this and not go broke :)

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