COMT (Val158Met) Mutation
COMT is the gene’s official symbol for the gene “catechol-O-methyltransferase”. The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones. In the brain, catechol-O-methyltransferase helps break down chemical messengers called neurotransmitters which are responsible for conducting signals from one nerve cell to another.
Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.
Catechol-O-methyltransferase (COMT; EC 220.127.116.11) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene.
Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.
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.
COMT & Estrogen
COMT has also been demonstrated to play a role in estrogen metabolism through inactivation of the catecholestrogens. Catecholestrogens are formed during the metabolism of estrogens such as estradiol. Catecholestrogen inactivation decreases 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. Additionally, COMT polymorphisms have been shown to influence estradiol levels. 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. Estradiol clearance is also diminished in both the Met/Met and Met/Val genotypes as opposed to Val/Val genotypes, however there is no significant difference in estrone levels.
The Val108/158Met polymorphism has been associated with other disorders that affect thought (cognition) and emotion. For example, researchers have studied this variation as a possible risk factor for bipolar disorder, panic disorder, anxiety, obsessive-compulsive disorder (OCD), eating disorders, and attention deficit hyperactivity disorder (ADHD).
Studies suggest that these conditions may be related to inefficient processing of information in the prefrontal cortex. There are however, many factors play a part in determining the risk of developing these complex disorders. Researchers have looked extensively at the potential connection between changes in the COMT gene and the risk of developing schizophrenia.
Most studies have focused on the effects of a particular common variation (polymorphism) in catechol-O-methyltransferase. This variation alters a single amino acid in the enzyme, replacing the amino acid valine with the amino acid methionine. In the longer form of the enzyme, this variation occurs at position 158 (written as Val158Met). In the shorter form of the enzyme, it occurs at position 108 (written as Val108Met). Researchers often shorten this notation to Val108/158Met. The change affects the stability and activity of catechol-O-methyltransferase, which alters the enzyme’s ability to break down neurotransmitters in the prefrontal cortex. Having valine at this position is associated with differences in thought processes that are common in people with schizophrenia, including problems with working memory, inhibition of behavior, and attention.
Other changes in the COMT gene may also contribute to these differences. Studies of the Val108/158Met polymorphism in people with schizophrenia have had mixed results. While most studies report no evidence of heightened risk with either methionine or valine at this position, some studies have found a slightly increased risk of schizophrenia in people with valine at position 108/158. A large number of genetic and lifestyle factors, most of which remain unknown, likely determine the risk of developing this condition.
- Agata R. et al. The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women. Maturitas 2016; 84:42–54.
- Crooke P et al. Estrogens, Enzyme Variants, and Breast Cancer: A Risk Model. Cancer Epidemiol Biomarkers Prev 2006; 15(9):1620-9.
- 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.
- Weinshilboum R et al. Methylation Pharmacogenetics: Catechol-O methyltransferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase. Annu. Rev. Pharmacol. Toxicol. 1999; 39:19-52.
- 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.
- 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.
- Mier D et al. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Molecular Psychiatry 2010; 15:918-927.
- Goldman D et al. The Genetics of Addictions: Uncovering the Genes. Nat Rev Genet. 2005; 6(7):521-532.
- 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.
- 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.
- Bhakta SG et al. The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophr Res. 2012; 140(1-3):192-197.
- Godar SC and M Bortolato. Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Front Behav Neurosci. 2014; 8:71.
- 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.
- Konishi Y et al. Genexgenexgender interaction of BDNF and COMT genotypes associated with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 51:119-125.
- 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.
- Lee SY et al. COMT and BDNF interacted in bipolar II disorder not comorbid with anxiety disorder. Behav Brain Res. 2013; 237:243-248.
- Zhang Z. The Val/Met functional polymorphism in COMT confers susceptibility to bipolar disorder: evidence from an association study and a meta-analysis. J Neural Transm. 2009; 116(10):1193-200.
- Janicki PK. Pharmacogenetics of Pain Management. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. Edited by TR Deers. American Academy of Pain Medicine. 2013.
- Zubieta JK et al. COMT val158met Genotype Affects mu-opioid Neurotransmitter Responses to a Pain Stressor. Science. 2003; 299(5610):1240-1243.
- Klepstad P et al. Genetic variability and clinical efficacy of morphine. Acta Anasthesiol Scand. 2005; 49:902-908.
- Mannisto PT 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.
- Corvol JC et al. The COMT Val158Met polymorphism affects the response to entacapone in Parkinson’s disease: a randomized crossover clinical trial. Ann Neurol. 2011; 69(1):111-118.
- Ball P and R Knuppen. Catecholoestrogens (2-and 4-hydroxyoestrogens): chemistry, biogenesis, metabolism, occurrence and physiological significance. Acta Endocrinol. Suppl. 1980; 232:1-127.
- Lakhani NJ et al. 2-Methoxyestradiol, a Promising Anticancer Agent. Pharmacotherapy. 2003; 23:165-172.
- Lavigne JA et al. The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNBA Damage Levels in Estradiol-treated MCF-7 Cells. Cancer Research. 2001; 61:7488-7494.
- 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.
- 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.
- Masurier M et al. Effect of Acute Tyrosine Depletion in Using a Branched Chain Amino-Acid Mixture on Dopamine Neurotransmission in the Rat Brain. Neuropsychopharmacology. 2006; 31(2):310-317.
- Sarris J et al. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord. 2014; 164:76-81.
- Kennedy D et al. Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacology (Berl). 2010; 211(1):55-68.
- Li Y et al. Functional and structural comparisons of cysteine residues in the Val108 wild type and Met108 variant of human soluble catechol O-methyltransferase. Chem Biol Interact. 2005; 152(2-3):151-163.
- Fava M et al. Rapidity of onset of the antidepressant effect of parenteral S-adenosyl-l-methionine. Psychiatry Res. 1995; 56(3):295-297.
- Jeffery DR and JA Roth. Kinetic reaction mechanism for magnesium binding to membrane-bound and soluble catechol O-methyltransferase. Biochem. 1987; 26(10):2955-2958.
- Sowa-Kucma M et al. Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims. J Affect Disord. 2013; 151(3):924-931.
- Basheer MP et al. A study of serum magnesium, calcium and phosphorus level, and cognition in the elderly population of South India. Alexandria J Med. 2016; 52(4):303-308.
- Yary T et al. Dietary magnesium intake and the incidence of depression: A 20 year follow-up study. J Affect Disord. 2016; 193:94-98.
- Haan MN et al. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: Results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2007; 85(2):511-517.
- Smith AD et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS One. 2010; 5(9):1-10.
- Mitchell ES et al. B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci Biobehav Rev. 2014; 47:307-320.
- Hiroi T et al. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun. 1998; 249(3):838-843.
- Zhu ZT et al. Tyramine excites rat subthalamic neurons in vitro by a dopamine-dependent mechanism. Neuropharmacology. 2007; 52(4):1169-1178.
- Burchett SA et al. The mysterious trace amines: Protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol. 2006; 79:223-246.
- Papaleo F et al. Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia. Eur Neuropsychopharmacol. 2015; 25(12):2349-2363.
- Almey A et al. Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav. 2015; 74:125-138.
- McCann S et al. Changes in 2-hydroxyestrone and 16α-hydroxyestrone metabolism with flaxseed consumption: Modification by COMT and CYP1B1 genotype. Cancer Epidemiol Biomarkers Prev. 2007; 16(2):256-262.
- Rižner TL. Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol. 2013; 381(1-2):124-139.
- Masurier M et al. Effect of Acute Tyrosine Depletion in Using a Branched Chain Amino-Acid Mixture on Dopamine Neurotransmission in the Rat Brain. 2006; 31(2):310-317.
- Fernstrom HD and MH Fernstrom. Tyrosine, Phenylalanine, and Catecholamine Synthesis and Function in the Brain. J. Nutr. 2007; 137(6):1539S-1547S.
- Reus G et al. Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. J Psychiatr Res. 2015; 68:316-328.
- Jangid P et al. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. 2013; 6(1):29-34.
- Lowe S et al. L-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI. Psychoneuroendocrinology. 2006; 31(4):473-484.
- Lardner A et al. Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders. Nutritional Neuroscience. 2014; 17(4):145-155.
- Mu W et al. An overview of biological production of L-theanine. Biotechnol Adv. 2015; 33(3-4):335-342.
- Kakuda T. Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction. Pharmacol Res. 2011; 64(2):162-168.
- Tian X et al. Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice. Brain Res. 2013; 1503:24-32.
- Martínez-Banaclocha M et al. N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? Med Hypotheses. 2012; 79(1):8-12.
- Dean O. et al. N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: Relevance to schizophrenia and bipolar disorder. Neurosci Lett. 2011; 499(3):149-153.
- Botsakis K et al. 17β-Estradiol/N-acetylcysteine interaction enhances the neuroprotective effect on dopaminergic neurons in the weaver model of dopamine deficiency. Neuroscience. 2016; 320:221-229.
- Tunbridge E et al. Polymorphisms in the catechol‐O‐methyltransferase (COMT) gene influence plasma total homocysteine levels. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 147.6 (2008):996-999.
- Paul R and A. Borah. The potential physiological crosstalk and interrelationship between two sovereign endogenous amines, melatonin and homocysteine. Life Sci. 2015; 139:97-107.
- Hursel R et al. The Role of Catechol-o-Methyl Transferase Val (108/158) MET Polymorphism (rs4680) in the effect of Green Tea on Resting Energy Expenditure and Fat Oxidation: A Pilot Study. 2014; 9(9): e106220.
- Lorenz M et al. The activity of catechol-O-methyltransferase (COMT) is not impaired by high doses of epigallocatechin-3-gallate (EGCG) in vivo. Eur J Pharmacol. 2014; 740: 645-651.
- Kang K et al. Beneficial effects of natural phenolics on levodopa methylation and oxidative neurodegeneration. Brain Res. 2013; 1497:1-14.
- Kang K et al. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: In vitro and in vivo studies. PLoS One. 2010; 5(8): e11951.
- Xie X et al. Adenosine and dopamine receptor interactions in striatum and caffeine-induced behavioral activation. Comp Med. 2007; 57(6):538-545.
- Witte A et al. COMT Val158Met polymorphism modulates cognitive effects of dietary intervention. Front Aging Neurosci. 2010; 2:146.
- Voelcker-Rehage C et al. COMT gene polymorphisms, cognitive performance, and physical fitness in older adults. Psychol Sport Exerc. 2015; 20:20-28.
- Zhu BT et al. Effects of tea polyphenols and flavonoids on liver microsomal glucuronidation of estradiol and estrone. J Steroid Biochem Mol Biol. 1998; 64(3-4):207-215.
- Moon YJ et al. Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism. Toxicol Vitr. 2006; 20 (2): 187-210.
- Ullah N et al. Green tea phytocompounds as anticancer: A review. Asian Pacific J Trop Dis. 2016; 6(4):330-336.