MTHFR. Do you have it? And is it affecting your health?

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MTHFR. This is something you may have heard of—it’s a gene that gets a lot of press. It can be very relevant for many people, and may be linked to symptoms like fatigue, depression, blood clots, OCD, poor memory, insomnia, and heart disease.1 But it also sometimes gets unfair blame. 

MTHFR stands for methylenetetrahydrofolate reductase. The gene codes for an enzyme that plays a crucial role in folate metabolism, and something called one-carbon metabolism. It has a very specific role – it converts a compound called 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. This is sometimes abbreviated as 5-MTHF, or sometimes it’s just called methy folate (or premethylated folate). Methyl folate is the primary form of folate found in the blood, and plays a number of key roles (which we’ll talk about more specifically at another time). For the purposes of this conversation, methyl folate is essential for something called methylation. Methylation is a key process that happens in every cell in our bodies. It is involved in protein synthesis, DNA, synthesis and repair, turning genes on and off, and maintaining general balance in the cells. If we think of the body as a car, I think of methylation as the oil in the engine—it keeps everything running smoothly. And if MTHFR is the central cog in the wheel of methylation, methyl folate is the lever that turns that wheel. Methyl folate is specifically involved in the remethylation of a compound called homocysteine to methionine, and we often measure homocysteine levels to get a sense of whether methylation is happening efficiently in the body or not. High homocysteine is associated with a number of health conditions – in particular, cardiovascular disease and impaired brain health.2,3

There are several common MTHFR SNPs that can lead to reduced efficiency of the enzyme. The two most common ones are often referred to as C677T and A1298C. The variant an individual has plays a big role in how efficiently the MTHFR enzyme works. A person can have one or two copies of either gene. Each copy of the A1298C gene variant decreases efficiency by about 15%; each copy of the C677T decreases it by about 35%. So someone who is homozygous for the C677T mutation—that is, someone who has two copies--has an enzyme whose activity is decreased by 70-80%.4–6

Some of these combinations tend to be more relevant than others. The C677T combination has been studied most, since it is the one that lowers enzyme activity the most. The compound heterozygotes are the group that is next most affected.

But there’s an important caveat with MTHFR. We think of MTHFR as a low penetrance SNP – this means that just because you have an MTHFR variant doesn’t mean that you are guaranteed to have problems. This gene variant is extremely common – some estimates suggest that up to 70% of the population carries at least one of these SNPs. The impact of MTHFR is affected by many dietary and lifestyle factors. Food quality is an important part of the equation, and foods naturally rich in B vitamins (especially folate, riboflavin, B12, and B6). It’s also affected by the function of other genes.

So, what do you do with MTHFR?

The first step is understanding your MTHFR status. Do you have one copy of the C677T SNP? Two copies? Are you a compound heterozygote? This can be determined with simple genetic testing (that can be done with bloodwork or a cheek swab), either through direct to consumer testing or through an integrative medicine practitioner. It’s helpful to look at the function of MTHFR in the context of other genes that are involved in methylation as well.

The second step is understanding the current function of the enzyme. Even if it has reduced capacity, diet and lifestyle can and do compensate for lower function. I have plenty of patients in my practice who fall into this category.

The clearest way to do this is by checking homocysteine levels, which can be done with a blood test. There are more advanced tests that can provide deeper insights in the overall function of methylation which we’ll talk about another time. A normal homocysteine is probably in the range of 7-9 micromol/L (it depends a bit on who you ask). If it’s higher, this may be an indication that decreased MTHFR activity is showing up and causing issues. It's worth noting, though, that homocysteine can be affected by other things too, like certain medications, decreased kidney function, and low thyroid function.

The B vitamins—especially riboflavin, B6, folate, and B12—are crucial to support MTHFR function. Sometimes targeted supplementation with these can help. Optimal support can be a complicated topic, and we’ll do another detailed dive into this. That’s when it’s especially helpful to work through the issue with an integrative healthcare practitioner.

So MTHFR is one part of the picture for many people. It’s usually not the only part—but you don’t know unless you test. And this is why I check MTHFR status in all my patients.

References

1.         Zhang YX, Yang LP, Gai C, et al. Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis. Front Psychiatry. 2022;13:976428. doi:10.3389/fpsyt.2022.976428

2.         Zarembska E, Ślusarczyk K, Wrzosek M. The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases. Int J Mol Sci. 2023;25(1):193. doi:10.3390/ijms25010193

3.         Peng F, Labelle LA, Rainey BJ, Tsongalis GJ. Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. Int J Mol Med. 2001;8(5):509-511. doi:10.3892/ijmm.8.5.509

4.         Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-172. doi:10.1006/mgme.1998.2714

5.         van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-1051. doi:10.1086/301825

6.         Chango A, Boisson F, Barbé F, et al. The effect of 677C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr. 2000;83(6):593-596. doi:10.1017/s0007114500000751