By Karen Raterman
The study of nutrigenomics is a relatively new. This science seeks to understand the connection between nutrition and gene expression and how both may impact the development of disease. One of the most intriguing findings from this research is the discovery of a genetic mutation that inhibits the production of the important enzyme MTHFR, or methylenetetrahydrofolate reductase. This enzyme is necessary for regulating the metabolism of folate in the body. When disrupted this can lead to the breakdown of homocysteine, a known marker for various health issues.
According to a National Institutes of Health study, as many as 11 percent of Americans have the MTHFR gene variation, with certain ethnic groups, such as Hispanics, being more predisposed to this condition.1 Given the broad impact of low folate in the body, clinicians now need to recognize the potential problems associated with this variation, assess their patients folate status, and ensure that they are receiving adequate amounts of the active form of folate to help mitigate their health risks.
The role of folate
Folate, or vitamin B9, is an essential water-soluble vitamin that occurs naturally in many foods and is also available in its synthetic form, folic acid. Though other nutrients can transport methyl groups, such as methionine, choline and vitamin B-12, only folate is involved in the transfer of single carbon groups, which are used to methylate DNA. This process is now thought to be linked to gene expression and carcinogenesis.2
Under normal conditions, absorbed folate is metabolized to 5-methyltetrahydrofolate (5-methylTHF) in the intestine and liver. For most people, folic acid is metabolized to 5-methylTHF as it is absorbed by the intestine. It is then passed to the liver. At this point, it behaves identically to natural dietary folate.3 Folic acid is normally reduced to dihydrofolate and ultimately THF. This process is described in a 2012 review in the journal Advanced Nutrition:
“Once the THF coenzyme is formed from either folic acid or dietary folate, it is first converted to 5,10-methylene THF by the vitamin B6 dependent enzyme serine hydroxymethytransferase and subsequently irreversibly reduced to 5-methylTHF by methylenetetrahydrofolate reductase (MTHFR). This reaction is key to maintaining the flux of methyl groups for remethylation of homocysteine to methionine via the vitamin B-12 dependent methionine synthase reaction. ”4
In other words, MTHFR is responsible for converting folate into an active form that can be used by the body in a variety of processes, including DNA synthesis, RNA production, methylation of DNA, proteins, neurotransmitters, phospholipids and the remethylation of homocysteine to methionine. 5,6
This means that folate and DNA methylation are ultimately tied. Appropriate DNA methylation is critical for normal genome functioning. Aberrant DNA methylation appears in many human diseases including cancer, imprinting disorders and developmental disabilities, the review authors noted “The evidence suggests that low folate status is associated with decreases in global DNA methylation, which has in some studies been associated with an increased risk of cancer and other diseases.”7
What are MTHFR mutations?
When methylation does not occur properly, it is considered a genetic variation in DNA sequencing. This is referred to as single nucleotide polymorphism (SNP). SNPs in the gene that codes for MTHFR produces an enzyme with decreased activity and may result in the accumulation of homocysteine. This can impact the function of the nervous system, behavioral function and vascular health as well as contribute to birth defects and the development of chronic disease.8,9
While there are a variety of MTHFR mutations, the most well studied are C677T and A1298C. Having one copy of either is not associated to any particular health risk, but individuals with two copies of C677T or one of each may be at higher risk for cardiovascular-related health issues due to an inability to convert folate to support lower homocysteine levels.10 Given the increasing rates of folate deficiency, it is now estimated that between 15 and 30 percent of the population may have increased dietary methyl needs due to gene polymorphisms impacting their methyl metabolism.11
At the same time, mounting evidence indicates that the effects of folate on DNA methylation may put patients at risk for numerous health issues. In one 2013 study, researchers looked at the association between neural tube defects (NTDs), folic acid and methylation noting that folic acid supplementation decreases the prevalence of NTDs. The researchers also wrote that much evidence suggests that not only folates, but also choline, B12 and methylation metabolisms, as well as gene polymorphisms may be involved.12 Another study looked at the impact of folate exposure in the intrauterine environment in both early life and in the aging process. The researchers found potential for folate to modulate DNA methylation and help modify the risk of cancer. This research is under further investigation.13
Given the growing associations between folate status and MTHFR SNPs, clinicians should assess their patients’ folate status and MTHFR capability through a comprehensive blood chemistry assessment. Risk increases for patients with certain clinical symptoms including those with coronary heart disease, elevated homocysteine levels, migraines, depression and a history of miscarriage or an infant with a neural tube defect.14 Patients on certain medications may also be at higher risk of folate deficiency. These folate-depleting medications include analgesics, antacids, antibiotics, and medications for high blood pressure, diabetes and oral contraceptives. 15
A complete assessment of a patient’s diet is also important to determine whether diet modifications and folate supplementation might be helpful. Folate is found in a variety of foods, including dark green leafy vegetables, broccoli, asparagus, avocados, brussels sprouts, lentils, chickpeas, and black beans.
Patients with the MTHFR SNP also may need supplementation with the methylated form of folate. Those with the MTHFR SNP may also require a higher dose of folate. Still, it is key to first assess their intake from food because excess folic acid is often not well tolerated. An optimal multivitamin should contain 200-400 mcg of methylfolate; a prenatal vitamin should contain 600-800 mcg.
Though there is still much to learn about the synergistic relationship between folate, DNA methylation and the development of disease, evidence continues to support this connection. Evaluating a patient’s folate level is essential for identifying and supporting those with genetic variations in addressing a higher risk for chronic health problems.
- Wilcken B et al. Geographical and ethnic variation of the 677C˃T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7,000 newborns from 16 areas worldwide. J Med Genet 2003; 40(8):619-625.
- Nazki FH, et al. Folate: Metabolism, genes, polymorphisms and the associated disease. Gene. 2014 Jan 1:533(1):11-20.
- Crider KS, Folate and DNA Methylation: A review of Molecular Mechanisms and the evidence for folate’s role. Adv Nutr 2012 Jan; 3(1):21-38.
- Botto LD et al. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies.; A huge review. Am J Epidemiol. 2000 May 1;151(9):862-877.
- Jacob RA. Folate, DNA methylation, and gene expression; Factures of nature and nurture. Am J Clin Nutr, 2000 Oct;72(4):903-904.
- Ibid. Adv Nutr 2012
- Brustoilin S et al. Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res 2010 Jan;43(1):1-7.
- Aguilar B et al. Metabolism of homocysteine and its relationship with cardiovascular disease. J Thromb Thrombolysis 2004 Oct;18(2):75-87.
- Ibid. J Med Genet 2003
- Niculescu MD et al. Diet, methyl donors and DNA methylations: Interactions between dietary folate, methionine and choline. J Nutr 2002 Aug1;132(8):23335-23355.
- Imbard A et al. Neural tube defects, folic acids and methylation. Int J Environ Res Pub Health, 2013 Sep 17;10(9); 4352-89.
- LY A et al. Folate and DNA methylation. Antiox Redox Signal 2012 Jul 15;17(2):302-26.
- NIH Dietary Supplement Fact Sheet Folate. Accessed online at https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/.