SNP Highlight - MTHFR C667T and Hypertension

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 methylation cycle by converting folate and folic acid (synthetic folate) to 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), homocysteine metabolism (10), cardiovascular health and overall healthy aging (11).

MTHFR Activity and the Methylation Cycle

The MTHFR enzyme is the rate-limiting step of the methylation cycle (12) and decreased MTHFR activity will greatly impact downstream reactions, as well as contribute to the build-up of potentially harmful molecules, such as homocysteine (13). The MTHFR C677T (rs1801133) mutation affects the enzyme methylenetetrahydrofolate reductase, which is the rate-limiting enzyme in the formation of 5-methyltetrahydrofolate (5-MTHF), or methylfolate. If you have the C677T mutation, your ability to convert folic acid into methylfolate is significantly reduced. Furthermore, the folate metabolism pathway is directly involved in the re-methylation of homocysteine to methionine due to the donation of a methyl group from 5-methyltetrahydrofolate. When the body is not able to adequately metabolize folate, the ability to re-methylate homocysteine is also compromised, which may lead to higher than normal levels of homocysteine.

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 (14, 15), 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 (16). It is estimated that up to 85% of the general population has at least 1 MTHFR SNP variant that impacts this methylation process (17). In fact, individuals who carry either 1 or 2 risk alleles for the MTHFR C677T (rs1801133) 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.

Association Between Impaired MTHFR C667T activity and Hypertension

The presence of the MTHFR C677T mutation is correlated with high levels of homocysteine in the blood and urine. Of the numerous risk factors associated with the development of hypertension and its related co-morbidities, elevated levels of homocysteine, also known as hyperhomocysteinemia (homocysteine levels >10 μmol/L) is suggested to contribute to an increased risk for hypertension as well as cardiovascular diseases through homocysteine-mediated damage to vascular smooth muscle and endothelial cells. This damage, in turn, leads to arterial vasodilation dysfunction, impaired vascular integrity, an increase in blood pressure, both systolic and diastolic blood pressure, as well as accelerated atherosclerosis (18, 19). These findings have been demonstrated in both in vitro and in vivo studies. Moreover, large observational trials, including the Third National Health and Nutrition Examination Survey (NHANES III) and the Systolic Hypertension in the Elderly Program trial (SHEP), have shown that high levels of homocysteine may be an independent risk factor for the development of hypertension (20, 21).

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 cofactors of the methylation process. These include folate or folic acid. However, individuals with compromised MTHFR activity may want to avoid folic acid since SNP polymorphisms in the MTHFR gene may limit a person’s ability to convert folic acid into the active form of folate, L-methylfolate. Instead, individuals who are heterozygous or homozygous for the MTHFR C667T mutation may benefit from supplementing with the L-methylfolate form of folic acid as well as focus on obtaining adequate amounts of folate naturally from the diet by increasing their intake of green leafy vegetables, broccoli, legumes, and grass-fed lean meats. 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 support the methylation cycle. 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 cofactor 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, the 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, maintaining a healthy weight, 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.