SNP Highlight - MTHFR

Part of our Deep Dive Genetics Series

What is the Role of MTHFR in the Body?

The methylenetetrahydrofolate reductase enzyme, known as MTHFR, plays an essential role in the one-carbon metabolic pathway and the methylation cycle by converting folate and folic acid (synthetic folate) into the active form of folate, L-methylfolate. The methylation cycle consists of multiple biochemical steps that are involved in adding methyl groups (CH3) to various molecules including DNA, RNA, and some proteins (1). Additionally, this methylation process is active in most cells of the body and is an essential component of many of the body’s metabolic reactions (2). In addition to converting the different forms of folate we consume into energy, the methylation cycle functions as a component in numerous pathways such as neurotransmitter synthesis (3, 4), cognitive function (5, 6), immune function (7), inflammatory response (8), DNA protection and regulation (9), as well as cardiovascular health and overall healthy aging (10). 

What Can Affect MTHFR Activity?

While the methylation cycle may be affected by numerous factors such as drug and alcohol use, exposure to heavy metals and environmental toxins (11, 12), or poor diet (lack of co-factors such as vitamin B6 or vitamin B12), the most common cause of impaired methylation is due to variations in the MTHFR gene, known as single nucleotide polymorphisms or SNPs (13). The MTHFR enzyme is the rate-limiting step of the methylation cycle (14) and decreased MTHFR activity will greatly impact downstream reactions as well as contribute to the build-up of potentially harmful molecules, such as homocysteine. It is estimated that up to 85% of the general population has at least 1 MTHFR SNP variant that impacts this methylation process (15).

 Who Is Most Likely to Have a MTHFR Mutation?

The most widely known MTHFR SNP polymorphisms include rs1801133, the C677T mutation, and rs1801131, the A1298T mutation. Individuals who carry either 1 or 2 risk alleles for the rs1801133 (C677T) mutation have approximately 35% (heterozygous carriers, +/-) to 70% (homozygous carriers +/+) reduced enzyme activity and subsequently have an impaired ability to convert folate and folic acid into the active form, L-methylfolate as compared individuals with no risk alleles. The MTHFR A1298 SNP polymorphism appears to affect MTHFR activity, however, this impact is much less pronounced than the C677T polymorphism. Individuals who are homozygous for the rs1801131 (A1298T) SNP polymorphism are estimated to have 40% to 50% reduced enzyme activity (16), however, the strength of research supporting this decreased activity is limited and more research is needed. This discrepancy in the impact of the rs1801133 polymorphism and the rs1801131 polymorphism may be due to the location of the polymorphism within the gene as rs1801133 appears to be located in the promoter region, the region of the gene which regulates expression and therefore activity, as opposed to the regulatory domain or the conserved region of the gene. Even if an individual is homozygous for one or both of the MTHFR mutations they are not necessarily going to have chronic illness or other symptoms related to impaired methylation. There are multiple dietary and lifestyle changes that can help reduce the problems associated with impaired MTHFR activity.  

How you can support MTHFR activity and the methylation cycle.

One of the first steps in supporting the MTHFR enzyme as well as the methylation cycle is to ensure a diet that is adequate in nutrients that function as co-factors of the methylation process. These include folate or folic acid. However, individuals with compromised MTHFR activity may benefit from supplementing with the L-methylfolate form of folic acid since SNP polymorphisms in the MTHFR gene may limit a person’s ability to convert folate or folic acid into the active form of folate, L-metylfolate. Individuals who have issues with MTHFR also are prone to having low levels of vitamin B12. Along with folate, vitamin B12 is one of the most important nutrients that supports the methylation cycle. Vitamin B12 helps to convert homocysteine, a by-product in the earlier steps of methylation to methionine. When homocysteine levels become elevated a person is much more likely to develop inflammation. Individuals who have impaired MTHFR activity or who have low levels of vitamin B12 should ensure they consume a diet adequate in this nutrient or consider supplementing with the methylcobalamin form of vitamin B12 which does not require additional processing by the liver. Additional nutrients that help to support MTHFR and the methylation cycle include vitamin B6, which is a co-factor for another enzyme, serine methylhydroxytransferase (SHMT), that works along with MTHFR to breakdown and metabolize different compounds. Individuals who consume a gluten-free diet should pay attention to the amount of vitamin B6 they consume to make sure they are consuming adequate amounts. Also, magnesium found in dark leafy greens, avocados, and nuts, as well as choline found in eggs and poultry, both contribute to optimal methylation reactions.

Lifestyle changes that help to support methylation include avoiding exposure to cigarette smoke, limiting alcohol consumption, restricting the use of antacids, staying active, stress management, getting enough sleep, and reducing contact with pesticides and other harmful chemicals. 

Finally, supplementing with SAMe, a precursor to glutathione, an antioxidant that helps to protect the body’s DNA, should be considered by individuals with impaired MTHFR activity as they are also prone to very low levels of this important enzyme.

To test for MTHFR, check out our Nutrition Optimization, Cardiometabolic, or Detox panels

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