Pharmacogenetic studies of change in cortisol on ecstasy (MDMA) consumption

In this study we investigate the association of cytochrome P450 enzyme CYP2D6, catechol-O-methyl transferase (COMT, Val158Met) and serotonin transporter promoter (5-HTTLPR) genotypes on change in cortisol concentration following 3, 4-methylenedioxy-methamphetamine (MDMA, 'ecstasy') consumption. Forty-eight subjects (30 males, mean age 23 years), self-nominating regular clubbers provided 'in the field' pre- and post-clubbing biological samples and associated information. Of the 39 subjects who provided a post-clubbing urine sample, 21 were positive for MDMA. Plasma cortisol concentrations increased in subjects (n = 48) tested for cortisol, with changes being significantly greater in the MDMA-positive group (736.9 ± 83.2 vs. 350.9 ± 34.5 mmol/l, p = 0.001). We found a positive association between the low activity COMT genotype (Met/Met) and MDMA-induced change in cortisol and also between this and change in cortisol in the whole sample (p = 0.039, Bonferroni corrected). For CYP2D6, there was an association between genotype and change in cortisol, confined to subjects with MDMA-positive urine post-clubbing (p = 0.003, Bonferroni corrected). There was no association with 5-HTTLPR genotype. These associations suggest that chronic use of MDMA may lead to HPA axis dysregulation and that the magnitude of this may be moderated by genetic polymorphism, and warrant further investigation in a larger sample of those who consume the drug on a regular basis.     

Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population

Despite the common use of MDMA (ecstasy) in the UK, the mechanism underlying associated potentially fatal cerebral oedema is unclear. We used a new experimental approach working directly with clubbers to perform a study on 30 (17 male) experienced clubbers (mean 6.6 years of clubbing). Pre- and post-clubbing measurements were performed to compare plasma levels of pituitary hormones (vasopressin, oxytocin), plasma and urine osmolality, urinary pH, and plasma sodium and urea. Ecstasy consumption was confirmed by using urinary drug screening pre- and post-clubbing. MDMA was detected in the urine samples of 17 subjects, three of which tested positive during pre-clubbing tests. Mean plasma vasopressin concentration increased in the MDMA group (1.28 +/- 0.29 to 1.43 +/- 0.41 pmol/l), but fell in other participants (1.23 +/- 0.42 to 1.16 +/- 0.0.34 pmol/l). Similarly, mean plasma oxytocin concentrations increased after ingestion of MDMA (2.02 +/- 0.29 to 2.43 +/- 0.24 pmol/l), but fell in the group that did not use MDMA (2.17 +/- 0.36 pmol/l to 1.89 +/- 0.37 pmol/l). There was a significant group by time interaction for plasma osmolality and plasma sodium (p = 0.001 and p = 0.003, respectively) and between change in urinary osmolality (p < 0.001) and MDMA use, with the pattern of change being consistent with the induction of inappropriate vasopressin secretion (also known as SIADH) by MDMA. This report demonstrates SIADH in ecstasy-using "clubbers", which has important clinical implications.     

Association between catechol-O-methyltransferase functional polymorphism and male suicide completers.

Suicide has been suggested to involve catecholaminergic dysfunction and to be related to genetics. Catechol-O-methyltransferase (COMT) 158Val/Met polymorphism (GenBank Accession No. Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT activity, that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. In this study, we hypothesized that the COMT 158Val/Met polymorphism is associated with suicide. The study population consisted of 163 suicide completers (112 males and 51 females). We found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls (p=0.036), while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls (OR: 0.52; 95% CL: 0.31-0.89; p=0.016). However, this was not the case in females. Our results suggest that the Val/Val genotype is a protective factor against suicide in males.     

The relationship between childhood abuse and dissociation. Is it influenced by catechol-O-methyltransferase (COMT) activity?

Dissociation is a failure of perceptual, memorial and emotional integration that is associated with a variety of psychiatric disorders. Dissociative processes are usually attributed to the sequelae of childhood trauma although there are data to suggest that genetic influences are also important. Bipolar disorder (BD), a condition with a strong genetic basis, has also been associated with early psychological trauma. Since childhood trauma is a risk factor for both BD and dissociation, we tested for potential gene-childhood abuse interactions on dissociation in a pilot sample of BD probands and their affected and unaffected relatives (n=178). Dissociation was measured with the Dissociative Experiences Scale (DES II) and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). The BD and recurrent unipolar depression (MDE-R) groups showed higher levels of self-reported abuse and dissociation than their unaffected relatives. The low-activity Met allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene was associated with lower levels of self-reported dissociation. Further, the functional catechol-O-methyltransferase (COMT) Val158Met polymorphism interacted significantly with total CTQ abuse scores to impact perceived dissociation. The Val/Val genotype was associated with increasing levels of dissociation in participants exposed to higher levels of childhood trauma. The opposite was observed in people with Met/Met genotypes who displayed decreased dissociation with increasing self-reported childhood trauma. The current findings support the involvement of the COMT Val158Met polymorphism in mediating the relationship between trauma and psychopathology.     

Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait.

The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1+/-12.6 years) and 218 female (age 36.1+/-13.6 years) healthy volunteers, who were assessed with Zuckerman's sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype x gender interaction (F=5.330, df=2, p=0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.     

Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder

It has been postulated that the prefrontal cortex plays a key role in attention-deficit hyperactivity disorder (ADHD). The catechol-O-methyltransferase (COMT) enzyme degrades synaptic catecholamines and plays a specific role in the catabolism of prefrontal cortex dopamine. We investigated the association between the COMT valine (Val) 108/158 methionine (Met) polymorphism and the response to treatment with methylphenidate (MPH) in children with ADHD. This study included 124 children with ADHD in South Korea. Those patients who had an improvement after 8 weeks of treatment greater than or equal to 50% compared with the baseline ADHD rating scale scores before treatment were considered to be the 'good response' group. After performing genotyping for COMT, we examined the correlation of the COMT polymorphism with response to treatment with MPH using the chi test. We found that whereas 62.5% of the patients showing a good response to MPH treatment had the Val/Val genotype, 41.7 and 11.7% of the patients showing a poor response to MPH treatment as assessed by their teachers had the Val/Met and Met/Met genotypes (chi=6.58, d.f.=2, P=0.035). Our findings provide evidence of an association between the COMT genotype and MPH response as assessed by the teachers of children with ADHD.     

Impact of catechol-O-methyltransferase on prefrontal brain functioning in schizophrenia spectrum disorders.

The enzyme catechol-O-methyltransferase (COMT) has attracted increasing interest regarding a genetic disposition towards schizophrenias and as a modulator of prefrontal brain function. A common SNP in the COMT gene causes a Val to Met transition at AA158/AA108 (Val158Met), resulting in reduced COMT activity in Met allele carriers. An impact of COMT genotype on cognition has been well established; however, the exact nature of this influence has yet to be elucidated. The aim of this study was to determine whether COMT genotype affects an electrophysiological marker of prefrontal activation and neuropsychological frontal lobe measures in schizophrenia. To this end, 56 acutely psychotic in-patients with schizophrenia spectrum disorders were investigated. Patients with the COMT 1947AA (Met/Met) genotype (n=13) were compared to a carefully matched sample of patients with a G1947A (Val/Met) genotype (n=15); matching criteria included patients' age, handedness, gender distribution, diagnosis, and medication status. A small group of six homozygous Val allele carriers was additionally included to allow an assessment of possible gene-dosage effects. P300 amplitudes and latencies, as well as an electrophysiological marker of prefrontal brain function (NoGo-Anteriorization/NGA) and neuropsychological measures (Stroop Test, Verbal Fluency, Trail Making Test) were regarded. Homozygous Met allele carriers had significantly increased NGA values and fronto-central Nogo amplitudes compared to patients with at least one Val allele. They also tended to perform better in the Stroop task, as compared to the matched group of Val/Met patients. These results indicate that COMT genotype exerts a strong impact on prefrontal functioning and executive control in schizophrenia spectrum disorders.     

CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP

In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.     

The association between the catechol-O-methyltransferase Val108/158Met polymorphism and hyperactive–impulsive and inattentive symptoms in youth

Rationale

Hyperactivity, impulsivity, and inattention are major symptoms occurring in attention-deficit/hyperactivity disorder. This disorder is highly heritable, multifactorial, polygenic, and associated primarily with dysfunctions of dopaminergic, noradrenergic, and serotonergic systems.

Objectives

The present study tested the possible association of the catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) polymorphism with hyperactive–impulsive and inattentive symptoms in male youth.

Method

Polymorphism COMT Val108/158Met was analyzed in 807 male unrelated Caucasian young subjects: 231 healthy controls, 195 subjects with moderate hyperactive symptoms and 254 subjects with moderate inattentive symptoms, 111 subjects with severe hyperactive symptoms and 90 subjects with severe inattentive symptoms, all evaluated using Swanson, Nolan, and Pelham Questionnaire IV criteria.

Results

The frequency of the COMT genotypes, alleles, and the homozygous Met/Met genotype versus Val carriers (χ ² test with standardized residuals) differed significantly between subjects without and subjects with hyperactive–impulsive and inattentive symptoms. In addition, significantly higher hyperactive–impulsive and inattentive scores were found in subjects with the Met/Met genotype compared to carriers of other COMT genotypes. These significant results were due to the more frequent occurrence of Met/Met genotype or the Met allele in subjects with moderate and severe hyperactive–impulsive and inattentive symptoms compared to matched controls.

Conclusion

These results suggest that the Met/Met genotype or the Met allele of the COMT Val108/158Met, contributing to higher dopaminergic activity, are significantly overrepresented in subjects with moderate or severe hyperactive–impulsive and inattentive symptoms, and that this polymorphism is significantly associated with hyperactive–impulsive and inattentive symptoms in young boys and adolescents.     

Genetic polymorphisms of CYP2D6, CYP1A1, GSTM1 and p53 genes in a unique Siberian population of Tundra Nentsi

The purpose of this study was to establish the frequencies of CYP2D6, CYP1A1, GSTM1 and p53 polymorphic genotypes in Tundra Nentsi, which comprises the small group of indigenous people belonging to Northern Mongoloids and Caucasians of Western Siberia. A total number of 102 Tundra Nentsi individuals and 96 Caucasians of Western Siberia were genotyped by means of polymerase chain reaction-based assays. Mutated alleles comprising CYP2D6*4, CYP1A1Val, GSTM1*0 and p53Pro were analysed along with the wild-type alleles. The results showed the intermedial position of CYP2D6*4 allele frequency in Tundra Nentsi, compared to Caucasians and Orientals (0.07 versus 0.2, P = 0.0003; 0.07 versus 0.003, P = 1 x 10(-6), respectively). Thus, our data indicate that the intermedial position of Tundra Nentsi between Orientals and Caucasians most likely shows the Caucasian ancestral origin of CYP2D6*4 allele. Comparative analysis of p53Pro allele frequency showed the pronounced ethnic differences with geographic gradient. Though the frequency of p53Pro allele ranged from 0.17 in Tundra Nentsi up to 0.3 in Caucasians of Western Siberia (P = 0.002), which is in agreement with the previously reported radial distribution of the known genetic markers. No differences were found in the CYP1A1Val allele distribution among Caucasians of Western Siberia and Caucasoid populations presented in other studies, whereas the frequency of Val allele in Nentsi was 1.5-fold higher (P = 0.076) compared to the Japanese group. It was found that the frequency of GSTM1 null genotype in Tundra Nentsi was only 39.8%. The frequency of GSTM1 null genotype in females was higher than in males (0.27 and 0.50, respectively) but that difference was not statistically significant. Comparative analyses of the distribution of putative markers towards cancer susceptibility, CYP1A1Val, GSTM1*0 and p53Pro alleles, have shown that the healthy Tundra Nentsi population (Northern Mongoloids) have a low number of p53Pro alleles and GSTM1*0/*0 genotypes and a high level of CYP1A1Val alleles. Further investigations of gene polymorphisms in isolated Northern native populations would be valuable in clarifying the origin of Northern natives. All this is important for comparative analyses of pharmacogenetic data in Mongoloid populations.     

Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.     

Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome

Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-O-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMTL) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMTL is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158Val/Met polymorphism coding for COMT high/low-activity alleles. The COMTL allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, chi2=7.76, p=0.005) and obsessive-compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, chi2=7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMTL individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS.     

Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia

It has been shown that risperidone (+)-9-hydroxylation is enantioselectively catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine the effect of CYP2D6 genotype on (+)-9-hydroxylation of risperidone in schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)- and (-)-9-hydroxyrisperidone at steady state were quantified using LC/MS/MS and HPLC with alpha 1 acid-AGP chiral column, respectively. The CYP2D6*5(*5) and *10 alleles were identified using polymerase chain reaction (PCR) methods. Twenty patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated alleles. There were significant differences in the steady-state plasma concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype groups, while the CYP2D6 genotype did not affect the steady-state plasma concentrations of (+)-9-hydroxyrisperidone (p = 0.314) or (-)-9-hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9-hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study suggests that CYP2D6 activity strongly influences the steady-state plasma concentrations of risperidone and risperidone/9-hydroxyrisperidone concentration ratios but is unlikely to determine enantio-selectivity in the steady-state plasma concentrations of 9-hydroxyrisperidone in the clinical situation.     

Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior

OBJECTIVE: The genes of catalytic enzymes of dopamine, including monoamine oxidase (MAOA and MAOB) and catechol-O-methyltransferase (COMT), have been major candidates for genes that affect smoking behavior. In this study, we investigated the relationship between smoking behavior and four polymorphisms of these genes, the MAOA variable number tandem repeat polymorphism, the MAOA 1460 T/C polymorphism, the MAOB intron 13 G/A polymorphism, and the COMT Val158Met polymorphism. The association between the MAOB polymorphism and personality traits was also explored. PARTICIPANTS AND METHODS: The polymorphisms were genotyped in 451 healthy Japanese volunteers. Data on smoking habits were obtained from structured interviews. In addition to testing the association between each polymorphism and smoking status, epistatic and additive effects between two polymorphisms were also investigated. RESULTS: A significant association was observed between the COMT Val158Met polymorphism and smoking status. Male participants with the Val/Val genotype had a significantly higher risk of heavy smoking compared with those with other genotypes, although no significant association was observed in female participants. No evidence was obtained for an association between the MAO genes and smoking behavior, including epistatic or additive effects. No significant association was observed between the MAOB polymorphism and personality traits. CONCLUSION: This study may suggest a role of the COMT Val158Met polymorphism in smoking behavior in Japanese individuals.     

Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone

OBJECTIVE: To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. METHODS: In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. RESULTS: The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered. CONCLUSIONS: CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.     

Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazole in healthy male volunteers: a preliminary study

The aim of the present study was to evaluate the effects of polymorphisms in dopamine D2 receptor (DRD2) and cytochrome P450 (CYP) 2D6 genes on delta EEG power response to aripiprazole in healthy male volunteers. Seventeen volunteers were recruited according to the DRD2 Taq1A genotype, and separated into the following groups: homozygous wild-type (A2/A2, n = 7), heterozygous (A2/A1, n = 5) and homozygous variant-type (A1/A1, n = 5) groups. After enrollment in this study, they were genotyped for CYP2D6. The volunteers received single 10 mg oral doses of aripiprazole, in accordance with an open-label parallel group study design. Plasma levels of aripiprazole and its metabolite were determined and EEGs were obtained simultaneously. The pharmacodynamic parameter was absolute delta power in the Cz channel. The changes of delta power were not different according to DRD2 Taq1A genotypes. As to the CYP2D6 allele, the subjects had the following CYP2D6 genotypes: *10/*10 (n = 4), *1/*10 (n = 5), *1/*5 (n = 2), *1/*1 (n = 3), *2/*41 (n = 1), *2/*2 (n = 1), *2N/*10 (n = 1). Subjects exhibiting the *1/*5 and *1/*10 genotypes showed a trend toward high area under the plasma aripiprazole concentration-time curve (AUC), which was linearly related to area under the EEG response-time curve (AUEC). Our results demonstrate a need for further evaluation of the CYP2D6 genotypic effect on the pharmacodynamics of aripiprazole.     

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

The Val158Met polymorphism of human catechol-o-methyltransferase (COMT) is one of the most well-studied single-nucleotide polymorphisms in neuropsychiatry; however, findings are inconsistent due to human genetic heterogeneity. We created the first ‘humanized'' COMTVal158Met mouse lines, which carry either human COMT Val or Met alleles via gene targeting. The ‘humanized'' mouse model enables strict comparison of the physiological functions of the two alleles. Consistent with human observation, Met/Met mice exhibited a 30% reduction in enzymatic activity compared with Val/Val mice. On the basis of the reported differences in human Met and Val carriers across working memory, fear processes and sensorimotor gating, we examined these functions between sibling Met/Met and Val/Val mice. Val/Val mice exhibited robust reductions in spatial working memory compared with Met/Met mice in both sexes, with tolcapone treatment significantly reversing the Val/Val alternation deficits. Sex effects were observed in other behaviors, with male Val/Val mice exhibited lower prepulse inhibition compared with Met/Met mice, whereas female mice exhibited the opposite phenotype. Female but not male Met/Met mice exhibited reduced contextual fear, increased cued fear, and reduced extinction recall. Thus, these mice (1) support the argument that human COMT Val158Met polymorphism modulates behavioral functions and most importantly (2) exhibit the expected treatment effects supporting the ‘inverted U shaped'' dose response of catecholamine signaling on cognitive function. This model will be invaluable for understanding the effects of human COMT Val158Met polymorphism on cortical development and behavioral functions, and how this polymorphism modulates treatment response.     

Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia.

BACKGROUND: Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia. METHODS: We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry. RESULTS: The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017). CONCLUSIONS: Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility.     

Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis

In human studies, low COMT (catechol-O-methyltransferase) activity has been associated with increased sensitivity to acute clinical preoperative or postoperative pain. We explored the association between the COMT genotype and three chronic pain conditions: migrainous headache, fibromyalgia, or chronic widespread pain and chronic musculoskeletal pain. Furthermore, we evaluated whether COMT genotype affects the efficacy of opioids in chronic pain. After a systematic literature review, we carried out meta-analyses on the three chronic pain conditions. The efficacy of opioids was evaluated using a systematic review only. The meta-analyses showed that fibromyalgia or chronic widespread pain is the only type of chronic pain that could be associated with the COMT single nucleotide polymorphism rs4680 (Val158Met). Met158, which results in the low-activity variant of COMT, is the risk allele. In chronic clinical pain, the effect of the COMT polymorphism depends on the pain condition. Low COMT activity is not associated with migrainous headache or chronic musculoskeletal pain conditions, but it may increase the risk for fibromyalgia or chronic widespread pain. Low COMT activity increases opioid receptors and enhances opioid analgesia and adverse effects in some cancer pains. Findings from animal studies that have utilized COMT inhibitors elucidate the mechanism behind these findings. In rodent pain models, COMT inhibitors are pronociceptive, except for neuropathic pain models, where nitecapone was found to be antiallodynic. The complex interplay between enhanced adrenergic and dopaminergic activity in different parts of the nociceptive system probably explains the complicated actions of low COMT activity.     

Dopamine metabolism in adults with 22q11 deletion syndrome, with and without schizophrenia--relationship with COMT Val¹⁰⁸/¹⁵⁸Met polymorphism, gender and symptomatology

22q11 Deletion syndrome (22q11DS) is a major risk factor for schizophrenia. In addition, both conditions are associated with alterations of the dopaminergic system. The catechol-O-methyltransferase (COMT) gene, located within the deleted region, encodes for the enzyme COMT that is important for degradation of catecholamines, including dopamine (DA). COMT activity is sexually dimorphic and its gene contains a functional polymorphism, Val1??/1?? Met; the Met allele is associated with lower enzyme activity. We report the first controlled catecholamine study in 22q11DS-related schizophrenia. Twelve adults with 22q11DS with schizophrenia (SCZ+) and 22 adults with 22q11DS without schizophrenia (SCZ-) were genotyped for the COMT Val1??/1?? Met genotype. We assessed dopaminergic markers in urine and plasma. We also correlated these markers with scores on the Positive and Negative Symptom Scale (PANSS). Contrary to our expectations, we found SCZ+ subjects to be more often Val hemizygous and SCZ- subjects more often Met hemizygous. Significant COMT cross gender interactions were found on dopaminergic markers. In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores. These findings suggest intriguing, but complex, interactions of the COMT Val1??/1?? Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia.