Catechol O-Methyl Transferase
COMT 472 A>G / Val158Met
Allele frequency in population:
The 1000 Genomes Project Database reports a global frequency of 37% for the A allele (NIH).
Gene and SNP Summary
COMT encodes the enzyme, catechol-O-methyltransferase, which is responsible for attaching a methyl group to a catechol substrate, including dopamine and catechol oestrogens, using S-adenosyl methionine (SAMe) as the methyl donor. The A allele leads to a 3 to 4 fold reduced activity of the enzyme and has been associated with an increased risk for certain cancers including breast and ovarian cancer. The GA and AA genotype has also been linked to decreased resilience to environmental stressors and thus an increased risk for anxiety related mood disorders.
COMT Gene Detail
The COMT gene encodes the enzyme catechol-O-methyltransferase. Two versions of this enzyme exist, namely the membrane-bound catechol-O-methyltransferase (MB-COMT), which is the longer form, and is chiefly produced by nerve cells in the brain. In other tissues, including the liver, kidneys, and blood, a shorter form of the enzyme, soluble catechol-O-methyltransferase (S-COMT), is produced. This form of the enzyme helps control the levels of certain hormones.
In the brain, catechol-O-methyltransferase assists in the break down of neurotransmitters. Catechol-O-methyltransferase plays a particularly important role in the prefrontal cortex, which requires signalling by neurotransmitters such as dopamine and norepinephrine to function effectively. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.
Amongst other catechol products, the COMT enzyme is also involved in methylating (and thereby inactivating) catechol oestrogens; 2- and 4-hydroxylated oestrogens. This is the most active conjugation pathway for these catechol oestrogens, although they can also be conjugated by the process of glutathione conjugation and sulfation. The enzyme is thus integral in health detoxification of oestrogen products. COMT requires SAMe and magnesium as cofactors for this process of methylation.
The variant COMT 472 G>A SNP leads to a change in amino acid from a valine to a methionine at position 158 of the protein. The A (met) allele has been associated with a three- to four-fold decreased enzyme activity, and an increased risk for certain cancers and anxiety mood disorders.
A significantly increased risk for breast cancer was observed in postmenopausal women with the low-activity COMT A allele who had long-term use of oestrogen (greater than 30 months), early menarche (before age 12), and post-menopausal obesity.
The COMT A allele has also been associated with increased risk for endometriosis. In mental health, individuals with the A allele, specifically homozygous carriers have exhibited an enhanced vulnerability to stressful situations and may have an increased risk of anxiety type disorders when exposed to environmental stressors. Homozygous A allele carriers may also have a heightened pain sensitivity, or decreased pain threshold.
COMT is responsible for breaking down products of caffeine metabolism, and the A allele has been associated with decreased enzyme efficiency in this regard, thus leading to increased predisposition to feelings of anxiety related to high levels of caffeine intake. COMT A allele carriers would therefore be advised to limit total caffeine intake to not more than one cup of coffee per day and to exclude other sources of caffeine from the diet.
A allele carriers were also found to be at higher risk of oestrogen related cancers, especially when overweight or exposed to higher levels of oestrogen. It is thus important for individuals with the AA or AG genotype to ensure optimal weight management, while focusing on avoiding or managing total oestrogen exposure, including hormone replacement therapy (HRT). The intake of cruciferous vegetables such as broccoli and kale, have been found to improve oestrogen metabolism, especially in GA and AA individuals.
Interestingly, the use of green tea, specifically the compound, ECGC, when considering studies of weight loss and antioxidant effects, has been shown to have the greatest effect in A allele carriers. This is possibly due to the delayed clearance of the compound as a result of the slower enzyme activity.
Due to the higher risk of anxiety for A allele carriers, stress management is an important intervention strategy to improve resilience to environmental and psychosocial stressors.
As SAMe and magnesium are required to complete COMT reactions, it is important to ensure adequate magnesium intake as well as adequate intake of B vitamins for SAMe production.
Unbalanced Estrogen Metabolism in Ovarian Cancer
Zahid et al, 2014.