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

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