Methylation support: A focus on MTHFR polymorphisms and folate

The processes of methylation, also referred to as “one-carbon metabolism”, are the mechanisms through which methyl groups are transferred from one-carbon molecules to DNA, proteins, hormones, neurotransmitters, and other compounds that are required for fundamental physiological activity. (5)(71

As described in our previous article, ‘Methylation: How can it be supported by nutrition’, methylation reactions have been widely studied with respect to their roles in gene expression, DNA and RNA synthesis, protein synthesis, central nervous system development, immune function, detoxification, neurotransmitter production and metabolism, hormone homeostasis, and cellular metabolism and structure. (32)

This article will focus specifically on the role of the methylenetetrahydrofolate reductase (MTHFR) enzyme in methylation processes and the potential health implications of the relationship between folate and MTHFR polymorphisms.

The role of MTHFR

One of the driving steps of the methylation cycles involves MTHFR. It is the enzyme responsible for the conversion of 5,10-methyleneTHF to 5-methylTHF, which is the bioactive form of folate needed to remethylate homocysteine. This conversion is required for subsequent production of methionine and the universal methyl donor, S-adenosylmethionine (SAMe) from homocysteine. In methylation reactions, SAMe is the metabolite that donates its methyl group to hormones, neurotransmitters, and other epigenomic-modulating compounds (e.g., nutrients or pharmaceuticals), as well as to DNA via DNA methyltransferases (DNMT). (5)

Polymorphisms of MTHFR may non-exclusively lead to the reduction of enzymatic activity, the accumulation of homocysteine, the development of folate deficiencies, or the reduction of methylation activity as a whole. (110) Folate deficiency, and/or the accumulation of homocysteine, is associated with a plethora of conditions, and disrupted DNA methylation can increase the risk for developmental dysfunction in future generations, as well as the development of disorders from epigenetic modification. (5)

Folate appears to be of particular importance for normal methylation capacity.

MTHFR polymorphism and related conditions

Polymorphisms are variations in DNA that transpire naturally and that may modulate the expression of genes and proteins within a population. Single nucleotide polymorphisms (SNP) result in substitutions of a nucleotide in DNA sequences, which occur with approximately every 1000 base-pairs. They are the most common polymorphisms that predispose specific biological characteristics or traits, and can result in increased, decreased, or unchanged susceptibility to certain health conditions. (55)

The National Human Genome Research Institute succinctly describes that “genomics is the study of all of a person’s genes (the genome), including interactions of those genes with each other and with the person’s environment”. (78) While the human genome is 99.5% homogenous between individuals, genetic sequence variations in the remaining ~0.1-0.4% of the genome, either as a result of polymorphisms or epigenetic modulation, can lead to altered susceptibility to disease. (55)(143)

Approximately 14 polymorphisms of MTHFR have been identified to cause drastic reductions in enzyme activity, while the effects of more common polymorphism variants are less severe. (65) Two common variants are labeled as MTHFR C677T and MTHFR A1298C. (111) While the ‘CC’ is the most common MTHFR genotype, the presence of the ‘T’ allele (producing ‘CT’ or ‘TT’ MTHFR polymorphisms) can lead to increased serum homocysteine, lower serum folate, and suppressed MTHFR activity, particularly with the TT genotype. (45)(110)

In a 2014 meta-analysis, the worldwide prevalence of the T allele was estimated to be 24%, while the global prevalence of the TT genotype was estimated at 7.7%, though this varies based on geographic location and ethnicity. (134) While the A1298C variant can also lead to reduced MTHFR activity, (110) it may have a smaller effect on outcomes related to modified methylation than polymorphisms containing the T allele. (44) Mechanistically, the C677T variant becomes more thermolabile with an alanine-to-valine substitution at codon 222 in exon 4, while the A1298C polymorphism results from a conformational change from binding of the SAMe-regulatory domain and a glutamate-to-alanine substitution at codon 429 in exon 7. (95)(148)

As such, the focus of this article primarily pertains to MTHFR polymorphisms with the T allele.

Figure 1 presents data on the prevalence of the CT and TT genotypes across the Americas. Worldwide, the greatest proportion TT allele expression may be found in Mexico, Northern China, and Southern Italy. (120)

Figure 1. The prevalence of the MTHFR ‘TT’ genotype across North America and Mexico adapted from Table 1. (120)

The presence of the ‘T’ MTHFR allele may be associated with an increased risk for a variety of conditions, including in pregnancy and birth, as well as cardiovascular, inflammatory, neurological, and reproductive disorders. (65) For a more detailed list of these disorders, populations at particular risk, and hypothesized mechanisms of action, please refer to Tables 4 to 8 found at the end of this article in the Appendix. It is important to note that while the evidence in the tables present positive associations between the TT polymorphism and various conditions, in most cases, evidence conflicts with respect to the significance of these associations.

In addition to the increased risk for the disorders mentioned above, MTHFR polymorphisms are also associated with an increased risk of cancers of the bladder, breasts, cervix, colorectum, esophagus, hepatocytes, lungs, oral cavity, ovaries, pancreas, prostate, and stomach. (65)

MTHFR lab testing

While there is some debate on the utility of MTHFR lab testing, (68) some clinicians opt to order lab tests for patients particularly in the presence of high levels of homocysteine, or if the patient’s family has a genetic history of the polymorphism. (111) As a whole, the identification of the MTHFR polymorphism should not be used as a measure of an individual’s state of health as there is considerable debate over the association between the polymorphisms and the manifestation of health conditions.

However, genetic testing may provide an indication of any additional need for functional nutritional support, particularly if a patient is inadequately consuming folate. There are a variety of MTHFR lab tests available which may require either salivary or blood samples. A few examples are listed below:

With regards to motivating patients to make diet and lifestyle changes to improve folate status, interesting results were reported from a genotype-nutrition program in Japan from 2006-2015. Patients in the program were provided with information on their MTHFR genotype, as well as nutritional counseling. After four to 12 months of the intervention, individuals experienced significant increases in their serum folate levels and reductions in serum homocysteine, regardless of their MTHFR genotype. The effects were especially noticeable in patients with the TT genotype. Moreover, individuals with the CT and TT genotypes increased their folate intake from green leafy vegetables, while those of the CC genotype did not. (52)

Ultimately, these results highlight that identification and communication of MTHFR genotypes in conjunction with nutrition counseling may improve health behaviors related to nutritional interventions that support methylation processes.

As previously mentioned, however, the presence of MTHFR polymorphisms does not necessarily provide an indication of compromised methylation capacity. Rather, it has been proposed that the association between MTHFR polymorphisms and states of hypomethylation may occur primarily due to a lack of one-carbon metabolism nutrients, particularly folate. (24)

Some clinicians opt to order lab tests for patients to detect high levels of homocysteine or genetic history of the polymorphism.

The role of folate

As previously described, folate is the precursor for 5-methylTHF, which acts as a methyl donor to recycle homocysteine to methionine in the methylation cycles. (45) Even in the presence of more than one polymorphism, the intake of adequate folate can counteract the negative effects of increased homocysteine caused by reductions in enzymatic activity. (111) Folate supplementation of 400 μg per day can reverse states of hypomethylation, (86) while higher doses of 5 mg per day may increase DNA methylation after six months. (58)

As folate appears to be of particular importance for normal methylation capacity, it is important to stay informed on the recommended intake of folate to avoid deficiencies, as well as the supplementation protocols that may be beneficial to reduce potential health impacts of MTHFR polymorphisms.

Folate status

Clinicians typically measure serum folate (acute) or red blood cell (RBC) folate (chronic) levels to determine folate status, (45) The following figure provides general measures indicative of low folate status: (26)(40)(123)

Figure 2. Measures of low folate status in plasma and red blood cells.

The World Health Organization (WHO) has indicated that a normal range for plasma folate exists between 6-20 ng/ml (13.5-45.3 nM) for all age groups. (123) The WHO also recommends that women of reproductive age should maintain RBC folate levels more than 400 ng/ml (906 nM) to optimize the reduction in risk for neural tube defects (NTD) in future offspring. (18

It is important to note that falsely low measurements of RBC folate may be a result of vitamin B12 deficiency rather than a low folate status. (105) To assist in distinguishing between folate deficiencies and B12 deficiencies, clinicians can also measure the levels of methylmalonic acid (MMA) and homocysteine. In folate deficiency, homocysteine levels are elevated and MMA are in a normal reference range, but in B12 deficiency, both homocysteine and MMA are elevated. (6)

General intake recommendations: food sources and fortified foods or supplements

For healthy adults, the recommended daily allowance (RDA) of folate from food sources is generally accepted to be 400 μg of dietary folate equivalents (DFE) per day. (79) In women of childbearing age, the range of 450-650 μg of folate from natural food sources provides folate in sufficient quantities to optimize the reduction of risk of NTDs. (72) This range is closely aligned with the RDA for lactating and pregnant women (500 and 600 μg per day, respectively). (79)

The table below summarizes general recommendations for folate intake in healthy adult populations.

Table 1. Folate and folic acid intake summary in healthy individuals for maintenance. (79)

The National Institutes of Health published a list of natural dietary sources (not fortified) of folate containing high amounts of folate per serving. The top ten are listed in the table below. (79)

Table 2. Non-fortified foods with high amounts of folate per serving.

For every 10% increase in DFE originating from natural folate sources, plasma and RBC folate levels will increase by approximately 6-7% in females between the ages of 12 and 49 when consuming dietary sources of folate within ranges of 50-400 μg per day. (72) In other words, doubling the consumption of folate can incrementally increase plasma or RBC folate concentrations as much as 60-70%, though some sources show increases in plasma folate by 47% and RBC folate by 23%. (9) In healthy adults and elderly individuals, it has also been shown that doubling folate intake, can incrementally increase plasma folate by 22% and RBC folate by 21%. (81)

In contrast to natural food sources of folate, fortified food and many supplements contain folate in its more bioavailable form, known as folic acid. Folic acid is roughly estimated to be approximately 50-60% more bioavailable than folate, though this may range between 30-98% based on the food source. (10)(42) Thus, it is now commonly accepted that every 0.5-0.6 μg of folic acid is equivalent to 1 μg of folate. Therefore, the RDA for folic acid is 200-240 μg DFE for adults, 250-300 μg for lactating women, and 300-360 μg for pregnant women. (79)

Similar to folate, meta-analyses estimate that within ranges of 50-400 μg of folic acid per day, plasma folate concentrations rise by 63%, while RBC folate increases by 31%. For every 100 µg increase in folic acid intake, healthy adolescents and adults may experience increases in serum folate levels by 11.6%. (21) The administration of more than 400 μg of folic acid per day (equivalent to 600-640 μg DFE from natural folate sources) does not provide further increases in plasma and RBC folate levels in healthy adults. (27)

In a recent meta-analysis, it was shown that doses of 300-500 µg per day of folic acid increase plasma folate concentrations two-fold and steady-state concentrations are achieved by 13 weeks in healthy adolescents and adults. Similarly, average doses of 375–570 µg per day increase RBC folate concentrations 1.78-fold with steady-state achieved by 36 weeks. (21) Times to achieve steady-state are also based on the strength of the dose and the gender or pregnancy status of the individual.

For instance, it has been shown that short-term (12 weeks) and long-term (three years) supplementation of folic acid at a dose of 800 µg per day produce 5% and 10% lower RBC folate concentrations, respectively, in men than in women due to differences in lean body mass. (122) In healthy male volunteers, serum folate concentrations may reach steady-state in six weeks at doses of 200 µg per day, while it may take between 12 to 14 weeks at doses of 400 µg per day. (117) In non-pregnant women, 450 µg per day achieved serum folate steady-state after one week. In comparison, serum folate stabilizes after eight weeks at this dose in pregnant women. (12)

Time to achieve steady-state RBC folate concentrations are based on the strength of the dose and the gender or pregnancy status of the individual.

Folic acid supplementation for individuals with MTHFR polymorphisms

As previously discussed, the relationship between MTHFR polymorphisms and condition-based outcomes is complex. This complexity particularly extends to possible variations in response to supplementation and dietary interventions based on individual MTHFR genotypes and ethnicity. 

Meta-analyses show that baseline serum and RBC folate levels may be sequentially lower in TT, CT, and CC genotypes, (108) and that individuals with the TT genotype typically have lower responses to improvement in folate status after at least 400 μg DFE per day of folic acid compared with the CT or CC genotypes. (17) However, this relationship may also vary based on gender, baseline folate, baseline homocysteine, glomerular filtration rate, smoking status, (113) and ethnicity. (84)

For instance, in one trial, Mexican American men appeared to require more than the RDA of 400 μg DFE per day regardless of genotype (though the effect is particularly prominent with the TT genotype) to prevent decreases in serum folate and rises in homocysteine. (106) This relationship was not observed in Mexican American women, where 400 μg DFE per day normalized serum folate and homocysteine, (41) reinforcing the need for higher folate intake in men than women. In comparison, in young non-Hispanic American women, RBC folate levels were reduced with the TT genotype compared with the CC genotype following a depletion and repletion phase with the intake of 400 μg DFE, indicating an inverse relationship between the ‘T’ allele and a folate intake limited to the RDA in this population. (103) In addition, homocysteine only decreased in the CC group. Finally, African American women had lower blood folate following consumption of the 400 μg RDA or 800 μg compared with Mexican American and Caucasian American women. (84)

Overall, it appears that most supplementation trials provide support for the additional use of at least 400 μg DFE per day of folic acid for a period of at least three months to increase folate levels in individuals with MTHFR polymorphisms. 

At equivalent doses of ~400 μg per day, folic acid in the form of 5-MTHF has also been shown to produce higher serum folate and RBC concentrations than standard folic acid regardless of the MTHFR genotype, and therefore, may provide greater utility in normalizing folate status through increased bioavailability. (8)(43)(63)(87)(121)

The table below provides evidence supporting the use of folic acid/folate interventions to increase folate status in various ethnicities, as stratified by MTHFR genotype.

Table 3. Summary of response to folate protocols based on ethnicity and MTHFR genotype.

The bottom line

In summary, the presence of MTHFR polymorphisms may be linked to a variety of health conditions. Whether these associations are linked to reduced folate status, increased homocysteine, or dysregulated methylation capacity, ensuring the presence of adequate folate intake is of utmost importance. While the RDA for folate may generally meet the needs of 95% of the population, additional intake through foods or through folic acid and/or 5-MTHF supplementation may be needed to normalize folate levels in different ethnic groups, genders, and those with MTHFR polymorphisms.

Appendix

Table 4. Cardiovascular disorders with higher risk from MTHFR polymorphisms (A-level evidence)

Table 5. Inflammatory disorders with higher risk from MTHFR polymorphism (A-level evidence)

Table 6. Pregnancy and birth disorders with higher risk from MTHFR polymorphism (A-level evidence)

Table 7. Neurological disorders with higher risk from MTHFR polymorphism (A-level evidence)

Table 8. Reproductive disorders with higher risk from MTHFR polymorphism (A-level evidence)

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