Everything You Need To Know About The MTHFR Gene Variants, According To Experts
If you've read anything about the emerging fields of personalized medicine or precision nutrition—or used an at-home genetic test kit to learn about your ancestry or inherited health traits—you've probably heard about MTHFR genetic variants. And no, it's not shorthand for your favorite expletive.
These genetic variants (known more scientifically as single nucleotide polymorphisms, or SNPs) have gained attention for the way they affect your ability to process and use the essential B vitamin folate and, thereby, affect a globally important (i.e., literally affects whole-body health) biochemical process called methylation.
Having an MTHFR genetic variant doesn't necessarily mean you'll experience health issues—but if you do, there are often simple dietary and lifestyle strategies (including targeted supplementation) that can support your overall well-being.* Below, we break down which physiological processes are affected when an MTHFR gene variant is present, the health impact that may be associated with them, relevant clinical testing, and more.
What is MTHFR?
Before we dive into the genetic variants and what they mean, let's talk about MTHFR itself and its role in the body when everything is functioning optimally.
MTHFR, or methylenetetrahydrofolate reductase, is an enzyme that converts dietary folate (from foods like leafy greens) and folic acid (from fortified foods and certain supplements) into a bioactive, methylated form called 5-methyltetrahydrofolate (5-MTHF).*
This activated folate acts as a highly effective and required methyl donor and plays a key role in a biochemical process called methylation—i.e., the transfer of methyl groups (simple structures of one carbon and three hydrogen molecules) to and from different compounds to support overall health.*
Specifically, 5-MTHF donates a methyl group1 to the amino acid homocysteine to convert it to the amino acid methionine; and methionine, in turn, can be activated to form S-adenosylmethionine (SAM-e), which travels around the body donating methyl groups to a variety of acceptors and helping regulate the activity of our cardiovascular, neurological, reproductive, and detox systems in the process.*
Holistically, this process or path is known as the methylation cycle. And as Ashley Jordan Ferira, Ph.D., RDN, mbg's vice president of scientific affairs, explains, "that first step—bioactive folate donating a methyl group to transform homocysteine to methionine—is a rate-limiting step."*
What does that mean? Ferira shares more: "It means that without adequate methylated folate (5-MTHF) hanging around, homocysteine can't move along efficiently to its next critical step. It can build up, and the rest of the methylation cycle is also slowed or deprived as a result. As it turns out, that's a huge deal for your health."*
So what's the big deal? Methylation is a foundational biochemical process in the body (i.e., in our cells) that takes place approximately one billion times per second and plays a role in just about everything—from keeping homocysteine levels in check (which is directly relevant to our cardiovascular and neurological health) to manufacturing important compounds like neurotransmitters and the master antioxidant glutathione to influencing gene expression, says functional medicine physician Robert Rountree, M.D.* (Learn more about methylation here.)
What is the MTHFR gene variant?
The MTHFR gene provides instructions for the body to make the MTHFR enzyme. "Just like there are different alleles for all kinds of genes that contribute to the unique human you are, the same is true for gene variants that impact nutrients and their metabolism," explains Ferira. For MTHFR, there are two common variants or SNPs (changes in the DNA sequence) that affect the enzyme's activity. This means that MTHFR is less efficient at converting folate and folic acid into the active 5-MTHF form.
The most common variant in the MTHFR gene is called C677T. About 20 to 40% of white and Hispanic individuals in the U.S. have one copy of C677T, which reduces enzyme function by approximately 35%, while 8 to 20% of the population has two copies of C677T (one from each parent), which reduces enzyme function by up to 70%.
Another variant called A1298C is found in about 7 to 12% of the North American population and carrying two copies may reduce enzyme function by 40%. In total, approximately 150 million Americans have an MTHFR gene variation—that's 50% of the population!
Because the MTHFR enzyme is less active with these variants, this can directly contribute to poor conversion to active folate (5-MTHF), which can mean your methylation cycle isn't running efficiently or optimally. As Ferira alluded to earlier and echoed by Rountree, this may cause subsequent elevations in homocysteine.
But just because you have an MTHFR gene variant doesn't necessarily mean you'll experience health issues, emphasizes Rountree. "Having a genetic variant generates a hypothesis, and then you have to test that hypothesis by looking for biomarkers," he says. "Testing homocysteine levels is the one reliable marker we have to determine if we're getting enough folate to support optimal methylation."*
Elevated homocysteine—which, in addition to these unique gene variants, can be brought on by poor diet, toxin exposure, and other lifestyle factors—would indicate subpar methylation and a greater need for methylated, active folate and other useful methyl donors in the diet and from targeted supplements.*
Signs that could point to an MTHFR gene variant.
"Not everyone with MTHFR SNPs will have subpar methylation or functional folate status; however, the combination of an MTHFR SNP and a typical American diet will often lead to methylation issues," says functional medicine physician Karyn Shanks, M.D., who openly shared that she possesses a copy of the C677T gene variant.
Signs that you have an MTHFR gene variant have the potential to be quite diverse since methylation affects so many different bodily processes. Research is still evolving in this area, "but so are the exciting fields of precision nutrition and the practical implementation of nutrigenomics, like specialized bioactive betaine and B vitamin complexes, like mbg's methylation support+"* shares Ferira.
Should you test for MTHFR gene variants?
Testing for MTHFR variants is not widely recommended, unless you have excess levels of homocysteine. Unfortunately, it's not a genetic test commonly covered by health insurance. So if you're curious about your MTHFR status, Rountree suggests starting with a homocysteine test. It's a relatively cheap and easy blood test, and it can guide further testing.
"If homocysteine levels are subpar, then even if you do have a genetic variant, your body is handling it," says Rountree. If the opposite is true, and you're eating a healthy diet, he adds, "it's time to ask yourself, 'I wonder if there's a genetic reason for that?'"
In functional and integrative medicine, homocysteine levels less than 7 μmol/L2 are often considered optimal. But as Ferira explains, "Any biomarker range can be honed to optimize the individual's health when partnering closely with a health care practitioner, but generally speaking, the normal range for homocysteine is broader and also age-dependent. Most adults want to aim for less than 15 μmol/L." For older adults, the upper end of the normal range expands a bit (up to 21 μmol/L).
If you're seeking to support healthy homocysteine levels (for the sake of your heart, brain, or overall health), a genetic test may help you determine if your genes are playing a key role, or if you should examine other aspects of your diet (including intake of other activated B vitamins—like B6, B12, riboflavin, and folate) and lifestyle.* If you're interested in genetic testing, consider working with an integrative or functional medicine practitioner who can run a more comprehensive genetic panel and help make targeted recommendations based on those results.
How to boost folate levels & methylation with an MTHFR gene.
The MTHFR enzyme maintains a certain level of activity even when you have a genetic variant—it's just less efficient. Increasing folate intake from dietary sources may help compensate by increasing levels of overall folate in the body, according to registered dietitian Ali Miller, R.D. Folate-rich foods include leafy greens, broccoli, avocado, asparagus, beets, citrus, animal proteins (particularly beef liver), and legumes.
However, as Ferira further explains, "while food folate is great—and oh, by the way leafy greens and similar plants are chock full of other nutrients and phytonutrients too—the folate naturally intrinsic to foods is in the tetrahydrofolate form, while fortified foods have folic acid. To be clear: Neither of those are fully activated 5-MTHF folate. They require several conversion steps, one of which is via your MTHFR enzyme to be fully activated."
That's why taking a supplement that already contains the bioactive form of folate—5-MTHF, aka methylfolate—can help your body absorb and utilize this essential B vitamin more readily and fully than supplements containing regular (not methylated) folic acid.* Rountree has been using and recommending methylfolate in his clinical practice for the past 20 years.
Ferira explains that she also recommends methylated folate and other bioactive B's too, saying that approach helps "clear the noise of genetic variation and deliver effective nutrition solutions that are inclusive to everyone's genetic makeup."* Miller agrees, adding that methylfolate is the most directly beneficial supplement for people with this variant, but "other methyl donors can be helpful as well, such as methylcobalamin (methylated form of B12), B6, and choline."* Choline is a precursor to betaine, a major methyl donor in this methylation story.*
Holistic nutritionist and author Kelly LeVeque is also a personal fan of effective B vitamin complexes featuring methylfolate. She previously shared that when "the most bioactive forms are utilized, including methylation technology for folate and B12, this directly supports personal differences in B vitamin metabolism and cellular energy for all."*
The bottom line.
MTHFR genetic variants are extremely common (and thus, we think should be discussed more!) and can affect the conversion of dietary folate and folic acid into active 5-MTHF. In some individuals, this may not manifest in tangible ways, while in others it could cause a deficit of functional folate and affect the whole-body process of methylation, leading to extra homocysteine and more.
If you think you may have an MTHFR gene variant, talk to your doctor about a homocysteine test, which is a great indicator of your folate and methylation status. And remember, even if your results come back with room for improvement, the fix is often relatively simple: Eat a minimally processed diet with plenty of B-vitamin-rich foods and consider leveraging a high-quality, gene-focused supplement like mbg's methylation support+ that contains active betaine and B's including methylfolate (5-MTHF).*
Stephanie Eckelkamp is a writer and editor who has been working for leading health publications for the past 10 years. She received her B.S. in journalism from Syracuse University with a minor in nutrition. In addition to contributing to mindbodygreen, she has written for Women's Health, Prevention, and Health. She is also a certified holistic health coach through the Institute for Integrative Nutrition. She has a passion for natural, toxin-free living, particularly when it comes to managing issues like anxiety and chronic Lyme disease (read about how she personally overcame Lyme disease here).