Catechol-O-methyl transferase

About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.

No Association Between Schizophrenia and Polymorphisms in COMT in Two Large Samples

Abstract: OBJECTIVE: A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses. METHOD: They reviewed data from more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples. RESULTS: The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. CONCLUSIONS: The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

Abstract: Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality and functional genetic variants associated to cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline, 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ) and the Hospital Anxiety and Depression Scale (HADS) and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 ( IL28B ), indoleamine 2,3-dioxygenase ( IDO-1 ), serotonin receptor-1A ( HTR1A ), catechol-O-methyl transferase ( COMT ), glucocorticoid receptors ( GCR1 and GCR2 ), brain-derived neurotrophic factor ( BDNF ) and FK506 binding protein 5 ( FKBP5 ) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy–Weinberg equilibrium. Older age (p=0.018, hazard ratio per 5 years=1.21), presence of depression history (p=0.0001, HR=2.38), and subthreshold depressive symptoms at baseline (p=0.005, HR=1.13) increased the risk of IFN-induced depression. So too did TCI-personality traits, with high scores on fatigability (p=0.0037, HR=1.17), impulsiveness (p=0.0200 HR= 1.14), disorderliness (p=0.0339, HR=1.11), and low scores on extravagance (p=0.0040, HR=0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR=3.83) than patients with the CC ( HTR1A ) and Met allele ( COMT ) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR=3.25) had a higher risk of depression than patients with the G allele ( HTR1A ) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p= 0.0436, HR=1.88) and BDNF genes (Val/Val genotype: p=0.0453, HR=0.55) were associated with depression. Conclusions: The results of the study support that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

COMT and DRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders.

Abstract: In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser9 alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser9 allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102–107, 2000 © 2000 Wiley-Liss, Inc.

Kinetic studies on the O-methylation of dopamine by human brain membrane-bound catechol O-methyltransferase

Abstract: Km values for dopamine and S-adenosylmethionine (AdoMet) of human brain membrane-bound catechol O-methyltransferase are 3.3 microM and 3.1 microM, respectively. S-Adenosylhomocysteine is a very potent competitive inhibitor with respect to AdoMet with a Ki value of 1 microM. Product inhibition patterns strongly support a steady-state compulsory-order ternary complex mechanism in which AdoMet binds to the enzyme before dopamine. Inhibition of membrane-bound COMT by tropolone is competitive with respect to dopamine (Ki = 5 microM) and uncompetitive with respect to AdoMet and is consistent with this type of mechanism. The mechanism proposed is different from that suggested for soluble catechol O-methyltransferases.