COMT Gene

COMT gene (Catechol-O-Methyltransferase) codes for the essential COMT enzyme involved in the inactivation of catecholamines such as dopamine, norepinephrine and catecholestrogens. COMT helps the body get rid of excess Dopamine, Epinephrine, Norepinephrine and Estrogens. A homozygous mutation of the V158M allele is associated with a 40% reduction in COMT gene activity.

1-3 Scientific research has demonstrated that a common mutation in the COMT gene locus results in the conversion of the amino acid valine to methionine at position 158 and causes a dramatic reduction in the enzyme’s ability to metabolize these neurotransmitters and catecholestrogens. 1,4 The enzyme is notably active in the prefrontal cortex which is the area of the brain that gives rise to what we perceive as our personality, emotions, behavior inhibition, abstract thinking, and short-term memory. 5 Val (G) allele carriers have higher enzyme activity resulting in greater stress resiliency and lower dopamine levels. Met (A) allele carriers have lower enzyme activity resulting in reduced stress resiliency and higher dopamine levels. Heterozygous Val/Met allele carriers exhibit an intermediate enzyme activity.

Dopamine and epinephrine help to create alertness and attention and people with COMT gene mutations tend to get more irritable. Individuals with a COMT gene mutation are generally volatile susceptible to depression, anxiety, mood disorders and toxicity symptoms. Addiction is common with individuals carrying this mutation, medical experts recommend early and often discussions around drugs, alcohol and other addictive substances or behaviors.

Methylation supports the brain and nervous system through neurotransmitter synthesis and degradation, which is vital for improving stress resilience and stabilizing mood. If you have a COMT gene mutation, your recovery from stressful events might be harder than for someone without this mutation or without impaired methylation because you don’t metabolize stress neurotransmitters, such dopamine, epinephrine, and norepinephrine as rapidly.

Methylation imbalance produces varied reactions among patients, and thus differential treatment approaches must be considered. Dopamine is elevated for individuals under stress, and if you are a high-dopamine producer, you will do worse under stress compared to someone without impaired methylation because you have so much dopamine in your system.

A homozygous mutation may also affect the way patients process 5-L-Methylfolate and Methylcobalamine (B12); therefore, medical experts recommend that you have this gene tested in addition to the MTHFR (MethyleneTetraHydroFolate Reductase) gene, which is the gene with greatest impact on methylation.

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MENTAL HEALTH

Polymorphisms in the COMT gene have been implicated in association with various mental health disorders due to the resulting changes in dopamine levels. 1,2,5,6 Disorders that may be associated with this gene variant in some populations include drug abuse, 7 alcohol abuse, 8 schizophrenic symptoms, 9,10 obsessive compulsive disorder, 11 panic disorder, 12 post-traumatic stress disorder, and 13 bipolar affective disorder.

 

ESTRADIOL INFORMATION

The COMT gene has also been demonstrated to play a role in estrogen metabolism through inactivation of the catecholestrogens. 14 This inactivation step lowers the cancer-causing potential of these metabolites, while simultaneously increasing the amount of 2-methoxyestradiol, a metabolite that has been shown to inhibit the growth of breast cancer cells. 4,15,16 Additionally, COMT gene polymorphisms have been shown to exert an effect on estradiol levels. Patients receiving estrogen therapy should pay attention to this gene especially if they have a family history of estrogen related cancers.

17 As Met/Met allele carriers exhibit a 2-3 fold decrease in their ability to degrade catecholestrogens, this results in higher estradiol levels than Val/Val allele carriers. 4,18 Estradiol clearance is also diminished in both the Met/Met and Met/Val genotypes as opposed to Val/Val genotypes.

 

PAIN MANAGEMENT INFORMATION AND NEUROLOGICAL INFORMATION

COMT gene polymorphisms have also been linked to pain sensitivity. It has been suggested that a reduction in dopamine inactivation, such as is seen with the Met/Met genotype, results in higher levels of dopamine, leading to chronic stimulation of the dopamine receptors. This overstimulation may result in less endogenous opioids being produced that help to provide pain relief and euphoria. Therefore, Met/Met allele carriers perceive a higher level of pain, while Val/Val carriers have the greatest resistance to pain. Interestingly though, studies have shown that Met/Met allele carriers require less morphine to achieve pain relief, possibly due to the increase in µ-opioid receptors seen with this genotype, while Val/Val allele carriers require the most medication for pain management. COMT gene also has been shown to have an effect on L-DOPA therapy in Parkinson’s disease treatment. Commonly COMT gene inhibitors, such as entacapone, are utilized in Parkinson’s treatment to augment and prolong L-DOPA treatment. COMT gene polymorphisms affect the bioavailability of these medications, yielding an enhanced effect of entacapone in the Val/Val allele carriers as compared to Met/Met allele carriers.

 

References:

  1. Lachman H et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6:243-250.
  2. Weinshilboum R et al. Methylation Pharmacogenetics: Catechol-O methyltransferase, Thiopurine Methyltransferase, and Histamine NMethyltransferase. Annu. Rev. Pharmacol. Toxicol. 1999; 39:19-52.
  3. Mannisto P and S Kaakkola. Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors. Pharm Rev. 1999; 51(4):594-622.
  4. Dawling S et al. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens: Comparison of Wild-Type and Variant COMT Isoforms. Cancer Res. 2001; 61:6716-6722.
  5. Mier D et al. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Molecular Psychiatry. 2010; 15:918-927.
  6. Goldman D et al. The Genetics of Addictions: Uncovering the Genes. Nat Rev Genet. 2005; 6(7):521-532.
  7. Yuferov V et al. Search for Genetic Markers and Functional Variants Involved in the Development of Opiate and Cocaine Addiction, and Treatment. Ann N Y Acad Sci. 2010; 1187:184-207.
  8. Schellekens AF et al. COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence. Addict Biol. 2013; 18(2):344-356.
  9. Bhakta SG et al. The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophr Res. 2012; 140(1-3):192-197.
  10. Godar SC and M Bortolato. Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Front Behav Neurosci. 2014; 8:71.
  11. Pooley EC et al. The met158 allele of catechol-o-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis. Mol Psych. 2007; 12:556-551.
  12. Konishi Y et al. Genexgenexgender interaction of BDNF and COMT genotypes associated with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 51:119-125.
  13. Kolassa IT et al. The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Biol Psychiatry. 2010; 67(4):304-308.
  14. Ball P and R Knuppen. Catecholoestrogens (2-and 4-hydroxyoestrogens): chemistry, biogenesis, metabolism, occurrence and physiological significance. Acta Endocrinol. Suppl. (Copenh). 1980; 232:1-127.
  15. Lakhani NJ et al. 2-Methoxyestradiol, a Promising Anticancer Agent. Pharmacotherapy. 2003; 23:165-172.
  16. Lavigne JA et al. The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNBA Damage Levels in Estradioltreated MCF-7 Cells. Cancer Research. 2001; 61:7488-7494.
  17. Worda C et al. Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Human Reproduction. 2003; 18(2):262-266.
  18. Eriksson AL et al. The COMT val158met polymorphism Is Associated with Early Pubertal Development, Height and Cortical Bone Mass in Girls. Pediatr Res. 2005; 58(1):71-77.