COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition
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Abstract:
Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task.In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences.Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.Keywords:
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Background: Treatment of postoperative pain remains suboptimal. This is attributed, in part, to the individualized physiological and psychological perception of pain. Although the effect of genetic variation on pain is unequivocal, precise understating of the effect of multiple gene interaction is yet to be investigated. Catechol-O-methyltransferase (COMT) interacts with several neuroreceptors in the brain including the mu receptor (OPRM1). Hence, we sought to explore the gene-gene interaction effect of OPRM1 and COMT on postoperative pain and opioid dose required for pain management. Methods: We used genotypes and clinical data for 153 postoperative orthopedic trauma patients. For the COMT gene four single nucleotide polymorphisms (rs6269, rs4633, rs4818 and rs4680), three haplotypes (ACCG, ATCA, and GCGG), and two diplotypes (low and high pain intensity) were considered for their interactions with A118G of OPRM1 on postoperative pain and opioid consumption. Data were analyzed using descriptive statistics and multiple regression. Analyses were repeated including only the Caucasian subjects. Results: For postoperative opioid consumption; a significant interaction was found between OPRM1 and COMT rs4680 (b=0.093, p=.037) and OPRM1 and COMT rs4633 (b=0.097, p=.037). The interactions between OPRM1 and COMT rs6269 and OPRM1 and COMT diplotypes demonstrated trends toward significance (b=-0.075, p=.080 and b=0.071, p=.070, respectively). The results for OPRM1×COMT rs4680 and OPRM1×COMT rs4633 on opioid consumption were maintained even after restricting the analyses to only Caucasian subjects. For postoperative pain scores, a significant interaction was found between OPRM1 and the GCGG haplotype of COMT (b=-0.926, p=.017). The interaction between OPRM1 and COMT rs4818 demonstrated a trend (b=-0.755, p=.060). When the sample was limited to only Caucasian subjects, only a trend was observed for the interaction effect of OPRM1 and the GCGG haplotype of COMT on postoperative pain (p= .070). The interactions of OPRM1×ACCG haplotype and OPRM1×diplotypes of COMT also showed trends toward significance (b=1.110, p= .058 and b=0.831, p= .050, respectively). Conclusion: OPRM1×COMT interactions may influence the variability in postoperative pain and response to opioids. Individualized pain management based on genetic variation can be an effective strategy to maximize the usefulness of pain management.
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Tranylcypromine
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Depression
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In Brief BACKGROUND: Previous studies have associated the catechol-O-methyltransferase (COMT) enzyme rs4680 polymorphism with opioid consumption in the treatment of chronic cancer pain. In this study, we evaluated the association between COMT rs4680 and rs4818 polymorphisms and opioid consumption in the acute postoperative period after a nephrectomy. METHODS: Opioid consumption and pain scores were evaluated in 152 patients for 48 hours after nephrectomy. The genotype of each patient was determined using polymerase chain reaction on DNA extracted from blood samples. The association between rs4680 and rs4818 genotypes and opioid consumption was evaluated using general linear model regression analysis. All P values and confidence intervals were Bonferroni corrected for the 3 comparisons among genotypes. RESULTS: In the 24-hour period after surgery (COMT rs4680), patients homozygous for the variant Val/Val consumed 36% (95% confidence interval, 31%–41%) more opioids than patients homozygous for the Met/Met group (P = 0.009). No statistically significant differences among the 3 genotype groups were noted for pain scores or emesis medication use in the first 24 hours after surgery. There was a statistically significant increase in emesis medication use in patients possessing the CC genotype of rs4818 when compared to patients carrying the GG genotypes (P = 0.035). In the 6- to 48-hour postsurgery period, there was significantly higher opioid consumption in the high-activity homozygotes Val/Val than in the homozygous Met/Met group for COMT rs4680 (0–6 h: P = 0.005; 0–12 h: P = 0.015; 0–24 h: P = 0.015; and 0–48 h: P = 0.023). Patients in the homozygous GG group COMT rs4818 single nucleotide polymorphism showed statistically significant differences in opioid consumption in the first 6 hours after nephrectomy compared with heterozygous CG patients (P = 0.02). CONCLUSIONS: The genetic variant of the COMT rs4680 single nucleotide polymorphism is associated with variability in opioid consumption in postoperative nephrectomy patients. The COMT rs4818 polymorphism may prove useful in predicting emesis medication use postoperatively. Published ahead of print September 3, 2014.
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Abstract Catechol-O-methyltransferase (COMT) regulates extracellular catecholamines. A widely studied COMT single nucleotide polymorphism (rs4680) changes the translated amino acid from valine to methionine (Val158Met); the polymorphism has been shown to influence opioid use. The aims of this study were to investigate the influence of COMT Val158Met on the likelihood and dose of opioid use in adults with chronic pain. Adults with chronic pain consecutively admitted to an outpatient pain rehabilitation program were recruited for study participation (N = 298). Individuals were genotyped for COMT Val158Met (rs4680). The polymorphism was analyzed using an additive and codominant genotype model. The distribution of genotypes was 23% (N = 70) for Val/Val, 49% (N = 146) for Val/Met, and 27% (N = 82) for Met/Met (Hardy–Weinberg, P > 0.90). No significant association was observed between opioid use and genotype under the additive model; however, a significant association was observed under the codominant model ( P = 0.027). A post hoc comparison demonstrated that the Met/Met genotype was more likely to use opioids compared with the Val/Met genotype ( P = 0.0089). No significant association was observed between morphine equivalent dose and genotype under the additive model; however, a significant association was observed under the codominant model ( P = 0.0496). A post hoc comparison demonstrated that the Val/Met ( P = 0.019) and Met/Met ( P = 0.043) genotypes used greater morphine equivalent dose compared with the Val/Val genotype. This study extends key knowledge about the influence of the Met/Met genotype and Met allele on opioid use in adults with chronic pain.
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The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d') and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.
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Child sexual abuse (CSA) is an important problem worldwide. The reason of sex abuse is considered as multifactorial. Genetic contribution reported by recent studies is a significant evidence for this pathologic behavior. Catechol-O-Methyltransferase (COMT) is an enzyme in the metabolic inactivation of catecholamine and substances containing catecholamines such as dopamine, epinephrine, and norepinephrine. COMT polymorphism causes functional changes in COMT enzyme activity. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor usually synthesized from central nervous system neurons. With the effect of BDNF, dopamine and serotonin play important roles on neurogenesis, survival, and synaptic plasticity.This study aims to examine COMT Val158Met (rs4680) and BDNF Val66Met (rs6265) polymorphisms in CSA.This was a case-control study.Seventy paraphilic child sexual abuser patients and seventy age- and gender-matched healthy controls participated in this study. COMT Val158Met and BDNF Val66Met polymorphisms were genotyped by real-time polymerase chain reaction assay.COMT Val158Met genotype frequencies were determined as GG 31.4%, GA 45.7%, and AA 22.9% in patients; GG 24.3%, GA 45.7%, and AA 8.6% in controls; and exhibited a positive relationship between the groups (P = 0.018). BDNF Val66Met genotype frequencies were determined as GG 77.1%, GA 21.4%, and AA 1.4% in patients; GG 65.7%, GA 31.4%, AA 2.9% in controls; and no significant relationship was observed between the groups (P = 0.317).This research investigated COMT (Val158Met) and BDNF (Val66Met) in paraphilic child sexual offenders. A positive relationship was found for COMT gene; however, no significant relation was observed for BDNF gene between paraphilic sexual offenders and controls.
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