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Our Take On The MTHFR Gene


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

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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References:
[1]Levin BL et al. (2016). “MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature.” J Genet Couns. http://www.ncbi.nlm.nih.gov/pubmed/27130656
[2]Moll S et al. (2015). “Homocysteine and MTHFR Mutations.” Circulation. 132(1):e6-9. http://www.ncbi.nlm.nih.gov/pubmed/26149435
[3]Klerk M et al. (2002). “MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis.” JAMA. 288(16):2023-31. https://www.ncbi.nlm.nih.gov/pubmed/12387655
[4]Clarke R et al. (2012). “Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.” PLoS Med. 9(2):e1001177. https://www.ncbi.nlm.nih.gov/pubmed/22363213
[5]Kumar P et al. (2015). “Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.” Meta Gene. 6:72-84. https://www.ncbi.nlm.nih.gov/pubmed/26629412
[6]Teng Z et al. (2013). “The 677C>T () polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies.” PLoS One. 8(2):e55332. https://www.ncbi.nlm.nih.gov/pubmed/23437053
[7]Den Heijer M et al. (2005). “Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.” J Thromb Haemost. 3(2):292-9. http://www.ncbi.nlm.nih.gov/pubmed/15670035
[8]Gouveia LO et al. (2010). “MTHFR and the risk for cerebral venous thrombosis–a meta-analysis.” Thromb Res. 125(4):e153-8. http://www.ncbi.nlm.nih.gov/pubmed/19926119
[9]Pu D et al. (2013). “Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.” Autism Res. 6(5):384-92. http://www.ncbi.nlm.nih.gov/pubmed/23653228
[10]Boccia S et al. (2008). “Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review.” Am J Epidemiol. 167(5):505-16. http://www.ncbi.nlm.nih.gov/pubmed/18162478
[11]Yan L et al. (2012). “Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies.” PLoS One. 7(10):e41689. http://www.ncbi.nlm.nih.gov/pubmed/23056169
[12]Yang Y et al. (2015). “Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers.” Birth Defects Res A Clin Mol Teratol. 103(6):488-500. http://www.ncbi.nlm.nih.gov/pubmed/25808073
[13]Crider KS et al. (2011). “Folic acid food fortification-its history, effect, concerns, and future directions.” Nutrients. 3(3):370-84. http://www.ncbi.nlm.nih.gov/pubmed/22254102
[14]Hickey SE et al. (2013). “ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.” Genet Med. 15(2):153-6. http://www.ncbi.nlm.nih.gov/pubmed/23288205
[15]American College of Obstetricians and Gynecologists Women’s Health Care Physicians. (2013). “ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy.” Obstet Gynecol. 122(3):706-17. http://www.ncbi.nlm.nih.gov/pubmed/23963422
[16]Genetics Home Reference. “Homocystinuria.” https://ghr.nlm.nih.gov/condition/homocystinuria

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