Can This Gene Influence Your Risk of Heart Disease (COMT)?

The COMT gene codes for an enzyme called catechol-o-methyltransferase (also called COMT). As its name implies, COMT transfers a methyl group to catechol-containing compounds. COMT uses SAM-e as its methyl donor. Therefore, having either too little SAM-e, or too much S-adenosylhomocysteine (SAH) — which is formed when SAM-e loses its methyl group — results in inhibition of COMT [R, R].

The main function of COMT is to help break down catecholamines, a family of neurotransmitters that includes dopamine, norepinephrine (also known as noradrenaline), and epinephrine (also known as adrenaline) [R].

COMT also breaks down other catechol-containing compounds, including estrogen and its byproducts [R].

COMT is widely distributed in organs such as the brain, adrenal glands, liver, kidneys, lungs, intestines, and mammary glands [R, R].

The COMT gene encodes an enzyme of the nervous system that breaks down the neurotransmitters dopamine, norepinephrine, and adrenaline by transferring a methyl group to them, from SAM-e.

Catechol-Containing Compounds and Inactivation by COMT

Norepinephrine and epinephrine are two neurotransmitters and stress hormones released by the adrenal glands during the ‘fight-or-flight’ response. They prepare the brain for stressful situations by promoting arousal, alertness, fear, and memory. Additionally, they increase heart and breathing rate, blood and sugar supply to the muscles, and blood pressure [R, R].

Because the sustained simulation of their receptors increases pain, anxiety, and the risk of heart disease, it’s important to block epinephrine and norepinephrine transmission when it’s no longer needed [R, R, R].

Both neurotransmitters can be inactivated by removal via transporters or breakdown by COMT and other enzymes. Norepinephrine is preferentially inactivated by removal, while epinephrine is mainly broken down by COMT. In kidney arteries and the liver, COMT breakdown is the preferred mechanism for both neurotransmitters [R, R, R].

Dopamine is a neurotransmitter involved in multiple cognitive and behavioral processes such as executive function, motivation, reward, and movement control. Outside the brain, it helps relax the blood vessels, increase urine output, reduce gastrointestinal motility and insulin production, and regulate immune cell activity [R, R].

Importantly, dopamine must be quickly inactivated to terminate the signal. Failing to do so is associated with heart disease. In most parts of the brain, this is achieved through removal by transporters. In the prefrontal cortex, where dopamine transporters are much less abundant, dopamine breakdown by COMT accounts for over 60% of dopamine inactivation [R, R].

COMT breaks down the female sex hormone estrogen and its byproduct catechols, which prevents the formation of the cancer-causing compounds quinones. In turn, estrogens reduce COMT expression and activity. This may explain why COMT levels are lower in women, and also the differing effects of COMT in men and women [R, R, R, R].

COMT breaks down the neurotransmitters dopamine, epinephrine, and norepinephrine, as well as the female sex hormone estrogen and its byproducts.

Roles in Heart Disease

Epinephrine and norepinephrine play key roles in heart physiology, such as increasing heart rate and blood pressure. Although these mechanisms help prepare the body for stressful situations, their excessive activity may lead to conditions such as  heart failure, coronary spasm, and irregular heart rate. Moreover, their breakdown to quinones causes oxidative stress that damages the blood vessels [R].

At physiological doses, dopamine may help prevent heart disease by relaxing the blood vessels and increasing the amount of blood pumped by the heart. However, high doses tighten the vessels, and increase blood pressure and heart rate. In fact, dopamine is typically used to treat newborns with low blood pressure and heart arrest [R].

Estrogen and its byproducts protect from heart disease through both short-term and long-term effects. In the short-term, they can relax blood vessels; long-term, they can inhibit blood vessel response to injury, prevent clogged arteries, and lower blood fat levels [R, R].

Epinephrine and norepinephrine raise the risk of heart disease by increasing heart rate, blood pressure, and vessel damage. Dopamine has different effects on blood pressure and heart rate depending on the dose. Estrogen can protect against heart disease by lowering blood pressure and blood fat levels, and improving blood vessel function.

SNP Summary and Table

Primary SNP: COMT rs4680

• ‘G’ = Normal risk of heart disease
• ‘A’ = Increased risk of heart disease
• 41% of the world population has genotype ‘GG’
• In people with European ancestry, both alleles are equally frequent

Other Important SNPs 

COMT rs4818

• ‘C’ = Normal risk of heart disease
• ‘G’ = Reduced risk of heart disease
• Globally, 1 out of 2 people only carries the ‘C’ variant
• It is most common in European descendants to carry one copy of each allele

COMT rs4633

• ‘C’ = Normal risk of heart disease
• ‘T’ = Reduced risk of clogged arteries
• The genotype distribution is very similar to that of rs4680 for all ethnicities

Rs4680

By far, rs4680 is the most widely-studied COMT gene variant. Its minor ‘A’ allele encodes a less-stable protein that results in reduced COMT levels and activity [R, R].

This variant has been associated with an increased overall risk of heart disease, as well as a higher incidence of heart attacks, stroke, and thrombosis [R, R, R].

The ‘G’ variant was associated with increased risk of heart disease in women with depression, heart attacks in hypertensive men, and clogged arteries in women. The enhanced breakdown of protective estrogens could account for these effects [R, R, R].

A widely-investigated COMT underactive variant is generally associated with increased risk of heart disease, although the results are somewhat mixed.

Other Variants

The minor ‘G’ variant of rs4818 encodes a protein with reduced activity. This variant was associated with a reduced risk of heart disease in a large-scale American study [R, R].

The minor ‘T’ allele of rs4633 increases COMT expression. This variant has been associated with a reduced risk of clogged arteries [R, R].

Two other COMT variants have been associated with changes in the risk of heart disease.