Disease relevance of COMT

• After simultaneous consideration of all three genes and other well-established risk factors of breast cancer, the COMT genotype remained the most significant determinant for breast cancer development and was associated with a 4-fold increase in risk (95% confidence interval, 1.12-19.08) [1].
• Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors [2].
• BACKGROUND: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease [3].
• Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension [4].
• Including the high-activity COMT 158Val allele to this combination also lowered aggressive prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88) [5].

Psychiatry related information on COMT

1. COMT and the Development of Aggressive Behaviors: The val/met variant of the catechol O-methyltransferase (COMT) gene in association with low birth weight has been linked to early onset antisocial behaviors in children diagnosed with attention deficit disorder [6]. However, a posterior study has failed to replicate this[7]. Strous and colleagues have reported an association between the low activity COMT polymorphism and risk of aggression in schizophrenia [8].
2. Other associations:

• RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes [9].
• CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders [9].
• MAO-A and COMT polymorphisms and gene effects in narcolepsy [10].
• COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT [10].
• Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder [11].

High impact information on COMT

• Catechol O-methyltransferase (COMT, EC 2.1.1.6) is important in the central nervous system because it metabolizes catecholamine neurotransmitters such as dopamine [12].
• With selective inhibitors of COMT in combination with L-DOPA, a new principle has been realized in the therapy of Parkinson's disease [12].
• COMT also inactivates catechol-type compounds such as L-DOPA [12].
• Here we solve the atomic structure of COMT to 2.0 A resolution, which provides new insights into the mechanism of the methyl transfer reaction [12].
• Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors [13].

Chemical compound and disease context of COMT

• Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer [2].
• We also hypothesized that women who were both low-activity COMT genotype- and glutathione S-transferase (GST) M1- and/or T1 null would be at higher risk for ovarian cancer because the combination of these genotypes could theoretically lead to higher catechol estrogen exposure [14].
• The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study [15].
• These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD [16].
• Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease [15].

Biological context of COMT

• Indexes of deamination, sulfoconjugation, and O-methylation, with the exception of a reduced deamination of dopamine and the activities of COMT, MAO-B, and TL-PST were not different in the two groups [17].
• Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC [18].
• We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies [19].
• No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found [10].
• Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association [19].

Anatomical context of COMT

• There was a significant correlation between red blood cell COMT activities and the proportion of urinary metabolites excreted as 3-O-methyl-alpha-methyldopa when methyldopa was taken alone (r = 0.532; P less than 0.01) but not when it was taken with sodium sulfate (r = 0.153; P greater than 0.20) [20].
• Sequential conversion of estradiol to catecholestradiols and methoxyestradiols by cytochrome-P(450) (CYP450) and catechol-O-methyltransferase (COMT), respectively, contributes to the antimitogenic effects of estradiol on vascular smooth muscle cell (SMC) growth via estrogen receptor-independent mechanisms [21].
• By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-beta-galactosidase plasmids into COS-7 cells, we showed that 17-beta-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently [4].
• COMT also has been shown to influence prefrontal cortex processing efficiency [22].
• In this study, we investigated whether similar reductions occurred in a glial cell line (U138MG) and whether COMT protein and activity levels paralleled the reduction in COMT mRNA levels in MCF-7 cells [23].

Associations of COMT with chemical compounds

• Enzyme activity correlated positively with age in all brain areas for MAO (with both benzylamine and tryptamine substrates) but no consistent pattern of correlation was found for COMT and TH [24].
• Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants [25].
• Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake [26].
• OR486 (COMT inhibitor) also blocked the antimitogenic effects of estradiol in both the presence and absence of the CYP450 inducers [27].
• Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent [3].

Physical interactions of COMT

• DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability [28].
• PST and membrane-bound COMT were found to have the lowest Km values for both catecholamines [29].

Regulatory relationships of COMT

• Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions [30].
• Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism [31].
• Transgenic maize (Zea mays) plants were generated with a construct harboring a maize caffeic acid O-methyltransferase (COMT) cDNA in the antisense (AS) orientation under the control of the maize Adh1 (alcohol dehydrogenase) promoter [32].
• It was found that epidermal homogenates from vitiligo patients expressed higher levels of COMT activity than homogenates from healthy controls [33].
• These results are compatible with the conclusion that the genetic polymorphism which regulates RBC COMT activity may also regulate the level of human lymphocyte COMT activity [34].

Other interactions of COMT

• The breast cancer risk associated with individual susceptibility genotypes varied among the three genes and was highest for COMT, followed by CYP1A1 and CYP17 [1].
• These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal [19].
• Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG [3].
• The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese [35].
• We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes [36].

Analytical, diagnostic and therapeutic context of COMT

• PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT) [2].
• To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese [35].
• The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively) [37].
• Because of the small sample size of this study population, odds ratios of a small magnitude could not be completely ruled out; however, the results presented do not support a strong association between the COMT polymorphism and the risk of ovarian cancer [14].
• In a cross-sectional study of 181 pre- and 171 postmenopausal women without breast cancer, we examined the relationship of a functional polymorphism in catechol-O-methyltransferase (COMT; VAL-->MET) to mammographic density and other risk factors for breast cancer [38].

References