- What is a genetic variant?
- Understanding MTHFR variants
- How does a genetic variant expand in the population?
- Why MTHFR variants are so common?
- When and why MTHFR variants become a problem?
- How do I understand if my MTHFR variant is a problem?
- Why fertility issues?
- Stay away from folic acid
- Take care of lifestyle and exposures
- Take the right supplementation (if you need any …)
- Full range of methyl donors and their co-factors
- Pre-activated micronutrients
- Take home message
Following the wider availability and decreased cost of genetic testing, the topic of genetic variants got very popular and the defective genetic variants of the gene Methylen TetraHydroFolate Reductase (MTHFR) are by far the most discussed. Lost in the mess of the variable and often questionable contributions to the discussion, diagnosed carriers are now wondering: “Should I be concerned? How much? … of what?”
Getting oriented is complex because the communication on the topic is often biased, in part due to commercial interests. Thus, let’s try to understand the problem, if any.
What is a genetic variant?
Genetic variants are genetic traits that are different from the most common ones (called wild type) but occurring with high frequency (> 10%) and are therefore physiologic. In other words, they are not diseases, they are just “variants” from normal. Variants must be distinguished from “mutations” where a rare, single gene change may be responsible of a disease and, in some cases, may be passed to the offspring. We are not talking about that.
Back to variants (of normal …), they become relevant when
the change affects a gene coding for an enzymatic protein and generates an enzyme with a modified activity, usually with increased or decreased efficiency in its reaction. The activity of the mutated gene is functional by definition, indeed otherwise it could not expand in the population to a double-digit rate, thus these DNA changes are validated by the natural selection.
Understanding MTHFR variants
Each single gene is made of hundreds to thousands of nucleotides (DNA building blocks) and each sequence of 3 nucleotides constitute an information (called triplet). If any of the 3 nucleotides within a triplet is changed, the code it forms with the other two is as well changed. This change may cause a non-sense information, and it is not further expanded, or a new valid code, which may introduce a functional change in the protein. The change may affect any part of the gene either in its coding part or in its promoter, the segment of the gene containing info for the start of the transcription. Moreover, we carry two copies of each gene and the change may affect only one copy, called heterozygous, or both copies, homozygous, with more of effects from the change in the homozygous form.
The MTHFR gene is made of a sequence of 2’200 nucleotides and, in theory, any of them could be subject to a change (mutation). Indeed, many possible mutations and variants (common mutations) are described. What we are usually testing is just two of all these possible changes, namely at position C677 where it is possible to find instead a T (C677T variant) and at position A1298 where we can find a C (A1298C variant).
2 normal 677C
2 normal 1298A
|61%||Not tested||Not tested|
The C677 variant is known to generate a protein that is sensitive to heat inactivation and is less efficient on transforming Tetrahydrofolate (THF) into 5-methyl tetrahydrofolate (5MTHF). Carriers of homozygous C677T variant may have half of the normal enzyme activity.
The methylation defect from the A1298C variant is milder and less clear in the mechanism. Some people carry both variations in heterozygous form and exert an intermediate defect.
In any case, what we are testing is just a limited piece of a single gene whereas the actual function depends on the whole gene and on its promoter and on those genes collaborating on the same function. In summary, testing the C677T and A1298C variants provides very limited information.
How does a genetic variant expand in the population?
Indeed, any variant started as an occasional (by mistake) mutation of a certain gene in a certain subject and was amplified by transmission to the offspring of the mutated subject and thereafter to next generation, and so on. If the new character passing to the offspring was pathologic, this would have caused lower fertility and/or shorter life with lower chances to pass the new gene to the offspring and the gene could never reach a high prevalence. In summary, any gene circulating with high frequency is not pathologic by definition.
Moreover, in order to reach high penetration in the population, a new genetic variant is also expected to (and usually does or did in the past) generate an advantage, at least in the situations (time, place, environment) allowing their expansion.
Why MTHFR variants are so common?
The simple answer is that they (did?) generate sounding side advantages. In the case of MTHFR variants, resulting in decreased output of 5MTHF, one may argue that it was an advantage against malaria: Low folates causes a shorter half-life of red cells and the plasmodium has no time enough to complete the replication cycle. This may explain the wide diffusion of these traits in the Mediterranean population. Moreover, cancers are usually folate dependent and a decreased feed of activated folates may hamper their progression (slower development, less of metastases). The same may apply to the majority of genetic variants, the larger their frequency, the more the side benefits they bring. Just as an example, a study on Italian elite athletes demonstrated that they had an increased incidence of MTHFR variants, especially among those involved in endurance sports. A possible explanation is that MTHFR variants improve the aerobic bioenergetics. In summary, MTHFR variants are not the evil.
When and why MTHFR variants become a problem?
Although not generating any metabolic perturbance in the majority of the carriers, it is also true that in some cases the MTHFR variants truly associate with medical problems, starting from infertility and chronic degenerative diseases. In many cases the imbalance is reported by an increased concentration of blood fasting homocysteine, but major problems may occur also with a normal homocysteine. As a matter of fact, the majority of carriers do not suffer high homocysteine and many cases of high homocysteine occur without any MTHFR variant in place.
The possible reasons why the variants start to be a problem are 3:
- Other, associated genetic traits: A single genetic weakness, which would be easily compensated, may associate to other weaknesses so that the global genetic combination of a subject generates an unsustainable mix. We are testing only MTHFR and don’t know about the others. Of course, MTHFR is involved, but is not the cause, it is only an associated and contributing factor.
- Dietary mistakes: The only good diet is varied and equilibrated. The modern chaotic lifestyle may interfere with out feeding. Moreover, any of the very popular polarized diets (e.g. vegan, gluten free, low carb, etc.) introduce perturbations. These are very mild in the majority of subjects but may result significant in front of a weak (in that respect) genetic background.
- Environmental pollution: Almost all of the most discussed pollutants, including bisphenol and derivates, dioxin and heavy metals are actually affecting the one carbon metabolism, including the MTHFR pathway, and add a functional request that may overcome the metabolic capacity of a weak subject.
In real life, usually variable combinations of the above 3 aspects are in place. It may happen that multiple genetic variants in the same pathway converge on the same subject generating a critical assembly. In these cases, a toxic load may generate a metabolic collapse. Such collapse is predicted to occur at time of increased demand, which in the case of the one carbon metabolism is at time to reproduce. This is important because metabolic issues unmasked at time to conceive (infertility) should be assumed as an alarm sign for the future metabolic health independently of the reproductive outcome.
How do I understand if my MTHFR variant is a problem?
Roughly … you can’t understand it. If you read the above, you may have understood the complexity of this topic. The genetic test itself does not diagnose any diseases and, doesn’t matter how many of your genes you test, nobody will be able to tell you what the findings mean from a metabolic point of view. Rather, we go by attempts based on the suspect from the epidemiologic studies highlighting the possible pathologic associations and factoring for the subject’s specific clinical findings. Thereafter, if a condition is described as associated to the MTHFR variants and clinical and lab findings (e.g. homocysteine) confirm the suspect, we try a folate supplementation. Sometimes it works (bingo!), sometimes it doesn’t because the methylation defect was not the main problem in that single subject. Should we insist in supplementing folates in these non-responders? We don’t know.
Why fertility issues?
It is simply a question of increased demand. The MTHFR enzyme stands in the middle of the one carbon metabolism (OCM), the most critical metabolic pathway for the life on this planet: The build-up of carbon units in molecules including DNA, RNA and amino acids (proteins) and the methylation of DNA that regulates its expression (epigenetics). Moreover, it regulates the endogenous generation of antioxidant activity and the production of energy in our mitochondria.
The demand for all of those metabolic activities increases several folds at time of gametes maturation and in the zygote post-fertilization, even more thereafter during the massive tissue expansion and differentiation of fetal tissues. The increased demand may cause the collapse of an otherwise equilibrated metabolism. This is relatively common and is the main issue in some infertile couples. I have personal experience of couples with 10+ years of infertility failing various cycles of assisted reproduction that achieved a spontaneous pregnancy once starting a due support with methyl donors.
This does not mean that we should test for MTHFR variants every couple. However, testing homocysteine is easy and cheap and may provide resolutive information in some cases. It should be offered to every couple with infertility issues. Thereafter, in case of high homocysteine and/or other signs of defective methylations, testing MTHFR variants may provide fundamental directions for the remedies to implement.
Stay away from folic acid
Folic acid has been around for decades as a holy remedy against neural tube defects and at the end we forgot what it actually is. Folic acid is not a natural substance and does not occur naturally in our body. It is an industrial surrogate of physiologic folates that was selected in the sixties for fortification programs due to its low cost and high stability in pharmaceutical and food preparation. The problem is that, to be active in humans, it must be activated by a double passage of our enzyme Di-Hydro-Folate Reductase (DHFR). Being it a bad substrate for the enzyme, at high concentrations it blocks DHFR causing a defect of activity also for the natural (dietary) folates. This blockade can be very problematic if associated to another weakness, downstream, on MTHFR.
Due to the same problem, the efficacy of folic acid, e.g. in lowering homocysteine, is very limited. Thus, doctors started to increase the dose trying to force the metabolism. It is common to see prescription of 5 mg of folic acid per day compared to an actual daily need of 0.2 mg, i.e. 20 fold the physiologic amount! Such mega-doses can be a metabolic killer in carriers of MTHFR variants. We strongly suspect that many cases of couple infertility are linked to (unintended) excessive folic acid exposure from food fortification programs (and supplements) in subjects carrying some metabolic weaknesses.
Take care of lifestyle and exposures
Let’s skip the usual hot air from talk shows to focus on the real issues.
A varied diet is a must. Avoid polarized diets. Avoid caloric excess, especially when gametogenesis is the issue, because it causes mitochondrial dysfunction and energy failure (causing increased demand to the OCM). Smoking generates an increased demand. The excess of nicotine is compulsory eliminated by methylation and this consumes massive amounts of methyl donors. The same happens with the metabolism of alcohol. Assumptions should be avoided and/or compensated.
Be careful with your environmental exposures with a main attention to your home and your job because they are the situations of longer exposure. Bisphenol A is almost everywhere and heavy metals use to contaminate many of the foods that we consider otherwise very healthy. The list is too long to be reported and nobody has and exhaustive one. As a matter of fact, I have experience of couple infertility cases addressed only by finding and avoiding a “lethal” exposure. This may be the main problem in some cases.
Take the right supplementation (if you need any …)
Our metabolism is not a pizza, where the more you put on top, the more the taste at the end. Taking multiple supplements just following the fashion of the time is a shortcut to metabolic and health problems. They do not add their benefits (if any …), rather they interfere each other creating a metabolic chaos. Take only the supplement that you really need, possibly under the guide of a (true …) expert. Check the effects at the lab, when possible. Be very suspicious with long term supplementations, actually we don’t know the outcome.
Read carefully the label of your supplement even more if you are taking more than one. It is a common (stupid) practice of manufacturers to put some folic acid in every supplement they release and you will not know it without reading the label. I have seen patients stating no folic acid exposure and thereafter found exposed to massive doses from multiple supplements taken for different reason (one for the hair, one for the skin, one for the allergy … folic acid in each of them).
You might conclude that a nutrient is not of help to you just because you assumed a fake product. Discard any supplement without a clear label, try to understand whether it is a reliable manufacturing and if the content is reliable. Manufacturers are not obliged to check the content of their product and to verify that it stands over time, and usually they don’t. The problem is that supplements use to contain multiple substances that react and degrades each other and the content of a tablet may be different a few months later. Always prefer products where the expiry date is stated. Note if they label together hydrosoluble substances (e.g. vitamin C) together with liposoluble substances (e.g. vitamin E) that do not fit together … how do they do? Try to sum-up the amount of nutrients of your supplement and compare it to the mass of the tablet: you may discover that only actives are contained (labelled) without excipients, and it cannot work.
In case of doubts question the manufacturer, it is your right.
Full range of methyl donors and their co-factors
Let’s assume that you carry a MTHFR variant with signs of methylation defect (e.g. increased homocysteine). The metabolite that you are poorly producing and that you may need to integrate is 5MTHF. A simple 5MTHF supplement may be enough in some cases, but: What if it does not work (enough)? A little increase of the dose may help to some extent but going further up makes no sense. Once you have saturated the need a further increase is an interference and, if the problem is still there, there may be something else … and this is the common case. As explained, MTHFR variants are not per se a cause of problems, they become an issue because mixed with other factors, including other metabolic weaknesses. Vitamin B12 is at least as relevant as 5MTHF for methylations and betaine is an alternative feed to homocysteine re-methylation: any support on this side improves the methylation power and decreases the work load from MTHFR, it might be enough to balance. Moreover, all the above pathways also need the participation of other co-factors, B vitamins and zinc, whose daily need must be ensured. A full coverage of the need of the pathway increases the chances to address the problems, wherever they are, and, if physiologic amounts are used, no perturbances occur. In summary, why to go for metabolism-perturbing mega doses of folic acid if a better efficacy and safety can be achieved with a dedicated multivitamin support? It is just a question of awareness … and cost.
The one carbon metabolism, due to its central position in metabolism and in reproductive functions, is a concentrate of genetic variants and mutations that affect with high frequency all of the genes coding enzymes of the pathway. We are investigating MTHFR because it got popular following the neural tube defect issues, but other variants in the pathway are extremely common and, although carrying the same functional metabolic potential as MTHFR, they remain under-investigated.
Mutation of the enzyme activating B12 (MTRR) are quite common and may be lethal for methylations, even more if associated to MTHFR variants, but have no effect if the diet/supplement contains good amounts of pre-activated B12 (methylcobalamin or CH3-B12). The same applies to the DHFR variants which, in particular, also lead to greater sensitivity to interference from folic acid. Defective variants of the enzyme producing betaine (BHMT) create a big load on MTHFR, which disappears if the diet/supplement includes adequate betaine. More than 200 functional mutations of CBS, the enzyme transforming homocysteine in cysteine and then in the antioxidant glutathione, are described and may cause the largest increases of homocysteine. They are to a good extent compensated by extra dietary cysteines and vitamin B6.
Assuming homocysteine reduction as the efficacy parameter, combinations of pre-activated micronutrients are tremendously more effective (and likely safer) than any large dose of single substances. In recent clinical studies, such combination achieved homocysteine reduction in 100% of exposed subjects both in infertile women (Schiuma 2020) and men (Clement 2023). In infertile women undergoing assisted reproduction, it was also able to decrease the homocysteine in the follicular fluid, which correlated with improved outcomes (Kucuk 2023).
Take home message
In summary, the test MTHFR variants C677T and A1298C does not diagnose any disease and is of no utility in most cases. Do not undergo the test if you don’t have specific reasons to do so.
Don’t take any supplement just because you were diagnosed a MTHFR variant, likely you don’t need it.
The test should be considered in the work-up for diseases known to be significantly associated to the variants, starting from infertility, even more if associated to increased blood homocysteine. In these cases, the occurrence of such defective variants may suggest an appropriate supplementation.
Keep in mind that folic acid is not the supplement for you and may further jeopardize your health. Meantime, avoid toxic exposures, which is the main problem, and never ever give-up to an isocaloric, varied and equilibrated diet.