MTHFR – Why is there so much interest in this gene?


You may have heard about the buzz about the gene 5,10-methylenetetrahydrofolate reductase, or MTHFR for short. Thousands of studies have been published linking genetic variants, or mutations, in this gene, to hundreds of medical conditions. These medical conditions include cardiovascular diseases, blood clotting issues, psychiatric disorders, developmental disorders, pregnancy complications, and cancer. However, the existing scientific data do not support most of the claims made about such associations.

In this blog post, we break down the scientific literature to explain what we do know about MTHFR, why testing for variants in this gene is likely not necessary, and why you should be wary of alternative medicine and supplement companies that are spreading misinformation and profiting from it. 

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The Science Behind MTHFR

What is MTHFR?

MTHFR produces 5-MTHF, the primary biologically active form of folate.
MTHFR produces 5-MTHF, the primary biologically active form of folate.

MTHFR is the gene that encodes for the enzyme 5,10-methylenetetrahydrofolate reductase. Enzymes are proteins that speed up chemical reactions in the body. The MTHFR enzyme helps convert a form of folate (5,10-methylenetetrahydrofolate) into a different form of folate (5-methyltetrahydrofolate), the latter of which is the primary biologically active form of folate. It plays a role in synthesis building blocks of proteins, otherwise known as amino acids. Specifically, this form of folate helps convert homocysteine to methionine. It has also roles in DNA damage response and the function of the nervous system.

Common Variants in MTHFR

There are a few common MTHFR gene variants that can decrease the activity of the enzyme. In fact, 40% of individuals in the general population have one of these two common variants, C677T and A1298C. The C677T variant specifically results in a 30-70% reduction in enzyme activity, likely due to the fact that the alanine to valine amino acid change makes the overall enzyme more heat-sensitive. In contrast, A1298C results in a smaller reduction in enzyme activity through an unknown mechanism.

SNP IDMajor AlleleMinor AlleleMinor Allele Population Frequency*Amino Acid Change
rs1801133(C677T)CT34%C (Alanine) > T (Valine)
rs1801131(A1298C)AC31%A (Glutamine) > C (Alanine)

*Allele Frequency Aggregator (ALFA) Project

It is important to note that not all common genetic variants are disease-causing, especially if they are incredibly common in the human population. While individual C677T and A1298C variants do decrease enzyme activity, they generally do not cause health issues. Most individuals have no health issues (i.e. convert homocysteine to methionine) even if MTHFR is not working optimally. In fact, most individuals that have a single variant appear to have normal, or non-elevated, homocysteine levels.

In some cases, however, MTHFR activity may have decreased to very low levels, more likely in individuals with two copies of the MTHFR gene C677T variant. This can result in high homocysteine levels. Elevated homocysteine in the blood, otherwise known as homocystinuria, if left untreated, can result in abnormal blood clotting, brittle bones, and nearsightedness, and increased risk of having a child with a neural tube defect (spina bifida). Nevertheless, homocystinuria is rare, with 1 in 200,000 to 335,000 affected individuals worldwide. Moreover, homocystinuria can result from genetic mutations in other genes, such as cystathionine-beta-synthase (CBS). Finally, homocystinuria is easily detectable, as the symptoms include seizures and developmental delays. Thus, the condition is primarily diagnosed early in life and sometimes even as a birth defect.

There is a lot of interest in the MTHFR gene among people who used direct-to-consumer genetic testing services. Does this mean you should get tested for variants in this gene?

As mentioned previously, despite thousands of research articles that have linked MTHFR variants to hundreds of health conditions, most of the evidence is conflicting or inconclusive. For example, some early studies suggest that individuals with C677T and A1298C variants are more likely to develop heart disease. However, more recent studies and meta-analyses with larger sample sizes suggest the opposite. It is important to be wary. Moreover, the notion that a single, common genetic variant can cause hundreds of unrelated health problems is implausible. Ultimately, more research studies with larger sample sizes will need to be conducted before more conclusive claims can be made about the role, if any, of MTHFR variants in disease.

Currently, the American College of Obstetricians and Gynecologists does not recommend testing for MTHFR variants. It is also important to note that, generally there is no need for a genetic test because homocysteine levels can be measured directly with a simple blood test instead. If homocysteine levels are found to be abnormally high, treatment is simple. It’s possible to take a folate supplement, as this allows the body to bypass the need for the enzyme. In any case, you should follow the medical advice of licensed physicians.

Beware of what alternative medicine websites say

There are a number of websites run by naturopaths that make contentious claims about the role of MTHFR variants as risk factors for various diseases. For example, MTHFR.Net run by Dr. Ben Lynch is selling genetic tests and supplements to diagnose variants and treat supposed deficiencies. Another example is My Home MTHFR which sells a genetic testing kit for $150. Other websites sell overpriced supplements, like 5-MTHF, and claim to help treat “infertility, anxiety, depression, inflammation,” and so forth. Beware of misinformation.

Want to learn more about yourself?

Many of the health conditions MTHFR may or may not be associated with are unlikely to be caused by a single gene or genetic variants within that gene. Rather, most of these health conditions are complex, and likely the result of the effects of variants in many genes. For example, a recent genome-wide association study for coronary heart disease highlighted a role for genetic variants near other genes, including QKI.

Whole genome sequencing

At Nebula Genomics, our goal is to empower you to explore your genetic testing data. We offer a number of tools to allow you to answer any question that you might have about your DNA. You can easily examine a gene of interest to learn more, or you can use the genome browser to directly examine your data. You can also examine genetic variants in your MTHFR gene. Order your 30x whole genome sequencing kit today to start exploring your genome!

Did you like this article? If so, you might also like our blog post about APOE! Also, check our our post about how to use ClinVar!

If you are interested in identifying mutations in your genetic data, you might find the following DNA upload sites helpful:

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