Trait#96: MTHFR and blood pressure
Monday, April 26, 2021. Author FitnessGenes
Monday, April 26, 2021. Author FitnessGenes
Blood pressure refers to the pressure of blood circulating in our blood vessels.
To get an understanding of why blood pressure is important, it may be helpful to think of our cardiovascular system as similar to a plumbing network. Under this analogy, the heart is the central pump, which pumps out water (blood) around a network of water pipes (our blood vessels).
We need a certain amount of pressure in the water pipes, otherwise the water will not flow through the system and water will only slowly dribble out every time we open the tap/faucet. This pressure is created by the central pump.
By a similar token, the pumping action of our heart creates a pressure in our blood vessels and this pressure allows blood to flow into tissues and organs, thereby delivering them oxygen and nutrients.
Generally speaking, blood pressure is significantly higher in arteries (the blood vessels that take blood away from the heart to supply tissues and organs) compared to veins (which return blood back to the heart).
Accordingly, whenever we talk about blood pressure in healthcare, we are typically referring to the pressure of blood in arteries.
If you’ve ever had your blood pressure taken, you will notice that you received two figures e.g. 120 / 80 mm Hg. (Incidentally, “mm Hg” is short for “millimetres of mercury”, which is a unit of pressure).
The first figure (i.e. 120 mm Hg) is known as your systolic blood pressure. This is the pressure in your arteries during systole - when the larger chambers of your heart (called ventricles) contract to pump blood to your tissues and organs.
The second figure (i.e. 80 mm Hg) is known as your diastolic blood pressure. This is the pressure in your arteries when the ventricles of your heart are relaxing and filling with blood. As the heart is not actively pumping blood through your arteries at this time, your diastolic blood pressure is lower than your systolic blood pressure.
According to the American Heart Association, a healthy systolic blood pressure is below 120 mm Hg. A healthy diastolic pressure is below 80 mm Hg.
Blood pressures above these values are considered unhealthy, with higher blood pressures linked to an increased risk of cardiovascular disease. High blood pressure (above 130 mm Hg [systolic] or 80 mm Hg [diastolic]) is also referred to as hypertension. The table below shows how blood pressure measurements are classified.
High pressure within blood vessels over time causes damage to arterial linings. This may lead to atherosclerosis, whereby arteries become narrower and harder. In turn, this impairs blood flow to various tissues and organs.
For example, high blood pressure can damage and cause narrowing of the coronary arteries that supply the heart. This increases the risk of a heart attack, when blood flow to the heart muscle is compromised. Similarly, damage to blood vessels supplying the brain can lead to stroke. Blood vessels supplying the eyes and kidneys are also particularly susceptible to damage from high blood pressure.
As well as causing narrowing and hardening of blood vessels, high blood pressure can also weaken blood vessels, causing them to bulge. A bulging of an artery is known as an aneurysm. If an aneurysm bursts, it can have fatal complications.
In addition to harming blood vessels, high blood pressure puts extra strain on the heart, which has to work harder to pump blood around the body. Over time this causes thickening of the heart muscle, which causes it to pump less efficiently. This can lead to heart failure whereby the heart is unable to pump blood around the body effectively.
MTHFR stands for methylenetetrahydrofolate reductase – an enzyme that is involved in our metabolism of folate (Vitamin B9).
Folate (Vitamin B9) and folic acid from our diet undergoes a series of chemical reactions known as the folate cycle, which produces the active form of folate known as 5-methyltetrahydrofolate (5-methyl-THF).
5-MTHF is then used in another chemical cycle called the methionine cycle, which is important for making proteins, methylation reactions, and regulating blood levels of homocysteine – an amino acid linked to cardiovascular disease.
You can read more about the folate cycle in Homocysteine and your folate genes explained article.
Source: Skibola, C. F., Smith, M. T., Kane, E., Roman, E., Rollinson, S., Cartwright, R. A., & Morgan, G. (1999). Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proceedings of the National Academy of Sciences, 96(22), 12810-12815.
The specific role of the MTHFR enzyme is to produce 5-methyl-THF from its precursor in the folate cycle, 5, 10-methylene-tetrahydrofolate (5,10-methylene-THF).
In order to carry out this reaction effectively, the MTHFR enzyme requires the help of Vitamin B2 (riboflavin). To adopt the scientific lingo, we say that Vitamin B2 is a co-factor for the MTHFR enzyme.
The MTHFR enzyme is involved in the production of a key molecule called nitric oxide (NO).
Nitric oxide (NO) is an example of a vasodilator, a substance that causes blood vessels to dilate, thereby increasing blood flow. This has the effect of helping to reduce blood pressure by lowering the resistance to blood flow within vessels.
You can read more about NO and its effect on blood pressure in the Nitric Oxide and Blood flow article.
The mechanism by which the MTHFR enzyme affects production of NO is quite complicated. In basic terms, NO is produced by an enzyme called nitric oxide synthase (NOS).
In order to work effectively, the NOS enzyme requires a cofactor molecule called BH4 (tetrahydrobiopterin). We’ve encountered BH4 before in the BH4 Synthesis and Recycling trait article.
BH4 can be generated and recycled from a related molecule called BH2. This recycling process relies upon an enzyme called DHFR (dihydrofolate reductase), as well as the MTHFR enzyme.
Source: Kennedy, D. O. (2016). B vitamins and the brain: mechanisms, dose and efficacy—a review. Nutrients, 8(2), 68.
By regulating the recycling of BH4, the MTHFR enzyme influences the activity of NOS and the production of nitric oxide. This, in turn, affects the vasodilation of blood vessels and, consequently, our blood pressure.
Riboflavin (Vitamin B2) is one of the water soluble B-vitamins and is found naturally in many foods, including eggs, organ meats (liver, kidney), lean meats, milk, and green vegetables.
Grains and cereals are also often fortified with riboflavin.
Riboflavin is extremely important in the body as it forms two key enzyme cofactors: FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide).
As explained previously, cofactors are molecules that bind to and activate enzymes, thereby allowing them to catalyse chemical reactions in the body.
FMN and FAD are cofactors for several different enzymes involved in cell function, energy production, growth, and metabolism of fats and proteins.
FAD is also a cofactor for the MTHFR enzyme. Therefore efficient MTHFR activity requires a healthy dietary intake of riboflavin.
The MTHFR enzyme is encoded by your MTHFR gene.
A well-studied SNP (Single Nucleotide Polymorphism) within the MTHFR gene, known as C677T or rs1801133, causes a C to T change in the DNA code.
This gives rise to two different alleles – the ‘C’ allele and the ‘T’ allele. The ‘T’ allele codes for a MTHFR enzyme that is more thermolabile. This means it is more likely to degrade at high temperatures and shows lower enzyme activity.
On this note, studies suggest that people with two copies of the ‘T’ allele (i.e. the TT genotype) have 70% lower MTHFR enzyme activity compared to those with the CC genotype.
Those with one copy of the ‘T’ allele (i.e. the CT genotype) have 40% lower MTHFR activity compared to those with the CC genotype.
Lower MTHFR activity, in turn, is thought to reduce the production of nitric oxide (NO), which can affect control of blood pressure. In this respect, one study of patients undergoing heart surgery found that those with the TT genotype had blood vessels that produced less nitric oxide (NO).
Part of the reason for reduced MTHFR activity in ‘T’ allele carriers is due to reduced ability of the enzyme to bind riboflavin as a cofactor.
The effect of this is that when riboflavin levels are low, ‘T’ allele carriers are more likely to have reduced MTHFR activity. Despite this reduced ability to bind riboflavin, studies suggest that increasing riboflavin levels can help to restore MTHFR activity.
Studies have shown that people with two copies of the ‘T’ allele (rs1801133) of the MTHFR gene (i.e. the TT genotype) have higher systolic and diastolic blood pressures compared to other genotypes.
An analysis of 6,076 individuals enrolled in the Joint Irish Nutrigenomics Organisation project, for example, found that until 70 years of age, people with the TT genotype had higher blood pressures than those with the CT and CC genotypes.
Interestingly, this effect was not observed in subjects aged 70 and over. The most likely explanation for this effect is that blood pressure tends to rise with age anyway, due to gradual stiffening of arteries and other age-related factors. The age-related “confounding factors” mean that MTHFR genotype has a relatively less pronounced effect on blood pressure in older individuals.
The same study also observed the impact of riboflavin levels on blood pressure, to assess whether this interacted with MTHFR genotype.
Riboflavin levels can be assessed using a specialised measurement known as EGRAC (erythrocyte glutathione reductase activation coefficient). Using this measurement, individuals in the study participants were classified as having normal (EGRAC≤1.26), low (EGRAC 1.26–1.40) or deficient (EGRAC≥1.40) riboflavin levels.
Compared to people with the CC genotype and normal riboflavin levels, the study found that those with the TT genotype had a 1.6 and 3 times higher risk of having high blood pressure (hypertension) if they were deficient or low in riboflavin, respectively.
Interestingly, riboflavin levels did not significantly influence the risk of hypertension in those with CC or CT genotypes.
The above findings suggest that the MTHFR enzyme encoded by the TT genotype is particularly susceptible to reduced activity when riboflavin levels are low.
In turn, reduced MTHFR activity is likely to impair production of nitric oxide (NO), which may contribute to increased blood pressure.
Conversely, increasing riboflavin levels may ameliorate MTHFR activity and help to reduce blood pressure, particularly in those with the TT genotype.
In line with this, clinical trials have shown that TT individuals on antihypertensive medication experience greater improvements in blood pressure when taking riboflavin supplements.
For example, in one clinical trial, hypertensive TT subjects taking 1.6 mg/day of riboflavin (in addition to normal antihypertensive medication) over 16 weeks experienced an average decrease of 5.6 mm/Hg in systolic blood pressure compared to those taking a placebo.
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