catechol-O-methyltransferase Haplotypes Research Articles

Effects of childhood trauma on aggressive behaviors and hippocampal function: the modulation of COMT haplotypes.

Aggression is a commonly hostile behavior linked to the hippocampal activity. Childhood trauma (CT) exposure has been associated with altered sensitization of the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal volume，which could increase violent aggressive behaviors. Additionally, Catechol-O-methyltransferase (COMT), the major dopamine metabolism enzyme, is implicated in stress responsivity, including aggression. Hence, CT exposure may affect aggression through the effect on the hippocampal function, which might also be modulated by the COMT variations. This study examined whether both CT and haplotypes of COMT moderate hippocampal function and thus affect human aggressive behavior. We obtained bilateral hippocampal functional connectivity maps using resting state functional magnetic resonance imaging (MRI) data. COMT haplotype estimation was performed using Haploview 4.2 and PHASE 2.1. Then we constructed a moderated mediation model to study the effect of the CTQ × COMT on aggressive behavior. Three major haplotypes were generated from thirteen single nucleotide polymorphisms (SNPs) within the COMT gene and formed three haplotypes corresponding to high, medium, and low enzymatic activity of COMT. The results showed interactive relationships between the Childhood Trauma Questionnaire (CTQ) and COMT with respect to the functional connectivity (FC) of the bilateral hippocampus (HIP)-orbital frontal cortex (OFC). Specifically, CT experience predicted lower negative HIP-OFC coupling in the APS and HPS haplotypes corresponding to the medium and high enzymatic activity of COMT, but greater FC in the LPS haplotypes corresponding to the low enzymatic activity. We also observed a conditional mediation effect of the right HIP-OFC coupling in the link between COMT and aggressive behavior that was moderated by CT experience. These results suggest that CT and COMT have a combined effect on aggressive behavior through hippocampal function. This mediation analysis sheds light on the influence of childhood experience on aggressive behavior in different genetic backgrounds.

Association of Catechol-O-Methyltransferase Gene Polymorphisms and Haplotypes in the Levodopa-Induced Adverse Events in Subjects with Parkinson's Disease.

The presence of dyskinesia is the most common side effect of chronic administration of levodopa in Parkinson's disease (PD) subjects. Genetic polymorphisms in levodopa metabolizing gene, catechol-O-methyl transferase (COMT), is shown to influence the inter-individual variability in drug response and adverse events. In the present study, the association of COMT rs6269, rs4633, rs4818, and rs4680 polymorphisms and haplotypes on pharmacokinetics and adverse events with levodopa was investigated in 150 PD patients. The age of onset of PD was 58.00 ± 10 yrs. The most common side effect faced by 78% of the subjects was dyskinesia. The AUC of levodopa was found to be significantly higher in subjects with dyskinesia (1695 ± 113ng/ml/hr, p < 0.0001) than those without dyskinesia (1550 ± 122ng/ml/hr). We found that the frequency of subjects presenting dyskinesia was significantly higher in subjects carrying variant genotype of COMT rs6269, rs4633, and rs4680 than that with wild genotype and these subjects presented higher AUC of levodopa. In addition, in subjects with dyskinesia, the AUC of levodopa was found to be significantly higher with low COMT (ACCG) haplotype. The association of COMT rs6269, COMT rs4633, COMT rs4818, and COMT rs4680 variant genotypes with the risk of dyskinesia due to levodopa therapy showed an ROC AUC of 0.67 indicating the moderate prediction of dyskinesia (p = 0.0021) with these COMT variants. In conclusion, PD subjects carrying the variant genotypes of COMT strongly influence high levodopa-induced dyskinesia. Hence the genotyping of COMT before the levodopa therapy will be useful to reduce the adverse events associated with the chronic levodopa treatment.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Multifocal Analysis of Acute Pain After Third Molar Removal.

Background: To analyze the pain modulation capacity profile in a Brazilian population, the relationship between opioid receptor (OPRM1) and Catechol-O-methyltransferase (COMT) 1polymorphisms and pain modulation capacity was determined through preoperative pain modulation tests and acute postoperative pain control evaluation, swelling, and trismus in 200 volunteers undergoing lower third molar removal. Methods: Psychologic and clinical parameters were measured. Patient DNA was sequenced for single nucleotide polymorphisms in OPRM1 and COMT, and the salivary concentration of interleukin (IL)-2 (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was evaluated. Primary outcomes were the influence of all predictors on the fluctuation of pain intensity using a visual analogue scale (VAS), and swelling and trismus on the 2nd and 7th postoperative days. Preoperative pain modulation capacity (CPM), pain catastrophizing scale (PCS), body mass index (BMI), and surgery duration and difficulty were evaluated. Results: Salivary concentration of IFN-γ and IL-2 as well as the duration of surgery influenced the fluctuation of postoperative pain in the VAS, and in the sum of the differences in pain intensity test at 8, 48, and 96 h. BMI influenced swelling, while both BMI and COMT haplotype influenced trismus on the 2nd postoperative day. Conclusion: Polymorphisms in COMT, salivary concentrations of IL-2 and IFN-γ, BMI, and duration of surgery were predictors for pain fluctuation, swelling, and trismus on the 2nd day after lower third molar extraction. This therapy was effective in controlling inflammatory symptomatology after lower third molar extraction and ibuprofen was well tolerated by patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03169127.

S176. A PRELIMINARY INVESTIGATION OF COMT GENE INVOLVEMENT IN COGNITIVE FLEXIBILITY AND ATTENTION IN SCHIZOPHRENIA SPECTRUM DISORDERS

BackgroundSchizophrenia spectrum disorders (SSD) are often characterised by a plateau or decline in cognitive abilities early in the prodrome. The cause of developmental alteration remains unknown, and investigation of genetic involvement in cognitive function in these disorders may assist the understanding of the underlying neurobiological mechanisms involved. Variation at two single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) gene have previously shown an influence on COMT protein levels and cognition; rs4680 and rs4818. Here we investigate the influence of the nonsynonymous “Val/Met” SNP rs4680 and a second functional SNP, rs4818, on tasks of cognitive flexibility and attention.MethodsThe sample comprised 48 healthy controls (HC; age = 31.95 ± 12.80; 25 males, 23 females), and 43 with a diagnosis of SSD (age = 41.64 ± 10.36; 26 males, 17 females). Measures of cognitive flexibility and attention included the Wisconsin Card Sorting Test (WCST), Continuous Performance Test-Identical Pairs version (CPT-IP), Trail Making Test (TMT), and the D-KEFS Colour Word Interference Test (CWIT). Due to small cohort sizes, in our preliminary analyses we chose to compare people who should be most severely affected because of inheriting COMT haplotypes associated with poor cognitive functioning (GG rs4818 / GG rs4680: G-G haplotype) to those with haplotypes associated with better cognitive functioning (CC rs4818 / AA rs4680: C-A haplotype). Multivariate analysis of variance factors included COMT haplotype, diagnosis (HC and SSD), and gender, with Bonferroni correction for multiple comparisons; age was included as a covariate. Analyses were also conducted based on a non-functional SNP of the COMT gene; rs165599, as a negative control.ResultsSSD exhibited reduced cognitive performance compared to HC; F(4, 75) = 8.810, p < .001. Investigation of C-A haplotype revealed an interaction with diagnosis on cognitive performance; F(8, 154) = 2.075, p = .041; SSD had reduced performance compared to HC for the WCST, CPT-IP, and TMT in C-A haplotypes (all p < .05). COMT haplotype also interacted with gender on cognitive performance (C-A haplotype; F(8, 154) = 2.315, p = .023, G-G haplotype; F(8, 154) = 2.706, p = .008). Males who were C-A non-carriers and /or G-G haplotype (high COMT activity groups) performed better on CPT-IP (both p < .05) and worse on CWIT (both p < .05) compared to females. Control SNP rs165599 revealed no main effects or significant interactions (all p > .05).DiscussionThe role of the COMT gene in the cognitive abilities of SSD remains contentious as gene expression does not differ from a healthy population. This preliminary analysis revealed an interaction between diagnosis and COMT haplotype, however, this only reached statistical significance for the C-A haplotype, where SSD with C-A haplotype and C-A non-carriers had reduced performance compared to HC on most tasks except TMT. The different effects found across the tasks, which probed various elements of cognitive flexibility and attention, supports a nuanced role of COMT in cognitive function. Further, high COMT activity was beneficial for males on CPT-IP but not CWIT compared to females. Gender interaction remains a significant consideration in studies of the COMT gene, likely involving the catechol-estrogens which are substrates of COMT. As expected there was no significant results with control SNP rs165599, indicating that findings were due to the influence of SNPs rs4680 and rs4818 on COMT activity.

Impact of COMT haplotypes on functional connectivity density and its association with the gene expression of dopamine receptors.

Catechol-O-methyltransferase (COMT) affects brain connectivity via modulating the dopamine system, with an expected greater effect of haplotypes than single-nucleotide polymorphism (SNP). The action pathway from COMT to dopamine to connectivity is theoretically dependent on the gene expression of dopamine receptors. Here, we aimed to investigate the impact of COMT haplotypes on brain functional connectivity density (FCD) in hundreds of healthy young subjects, and to disclose the association between the COMT-FCD statistical map and the spatial expression of the dopamine receptor genes. We found an inverted U-shaped modulation of COMT haplotypes on FCD in the left inferior parietal lobule that is mainly connected to the frontal and parietal cortices, with APS homozygotes exhibiting greater FCD than the other five groups. However, we failed to identify any significant effect of any SNP on FCD. Utilizing gene expression data collected from Allen human brain atlas, we found the COMT-FCD statistical map was significantly associated with the expression patterns of the dopamine receptor genes. Our results suggest that COMT haplotypes have greater impact on functional connectivity than a single genetic variation and that the association between COMT and functional connectivity may be dependent on the gene expression of dopamine receptors.

Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease

ObjectiveCatechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for both motor and cognitive functions. Few studies have examined the association between COMT variants and cognition in patients with Parkinson's disease (PD). MethodsWe assessed a cohort of 409 PD patients without dementia who were regularly followed for two years. The Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE) were administered at baseline and during the follow-up. The genetic variants and haplotypes of COMT, including rs6267, rs6269, rs4633, rs4818, and rs4680, were examined. ResultsNo association was observed between COMT genotypes and baseline cognitive function. After a mean follow-up period of 647.3 days, MMSE scores deteriorated with age. Cognitive decline correlated with age (P < 0.05) but not with the motor severity defined using UPDRS part III scores (P = 0.21). Kaplan–Meier survival analyses showed that PD patients carrying the G allele of the rs6269 variant and COMT haplotypes constituting the G allele of rs6269 showed a significantly more rapid decline in the MMSE scores over the follow-up period (log-rank test, P < 0.01). Cox proportional regression analysis adjusted for covariates revealed that among patients with PD, those carrying the high-COMT activity haplotype (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) showed a high risk of cognitive decline (hazard ratio = 3.24; P = 0.02). ConclusionOur findings suggest that the high-COMT activity haplotype is associated with cognitive decline in patients with PD.

Catechol O-methyltransferase (COMT) functional haplotype is associated with recurrence of affective symptoms: A prospective birth cohort study

BackgroundCatechol-O-methyltransferase (COMT) polymorphisms play an essential role in dopamine availability in the brain. However, there has been no study investigating whether a functional four-SNP (rs6269-rs4633-rs4818-rs4680) haplotype is associated with affective symptoms over the life course. MethodsWe tested this using 2093 members of the Medical Research Council National Survey of Health and Development (MRC NSHD), who had been followed up since birth in 1946, and had data for COMT genotypes, adolescent emotional problems (age 13–15) and at least one measure of adult affective symptoms at ages 36, 43, 53, or 60–64 years. First, differences in the levels of affective symptoms by the functional haplotype using SNPs rs6269, rs4818, and rs4680 were tested in a structural equation model framework. Second, interactions between affective symptoms by COMT haplotype were tested under an additive model. Finally, a quadratic regressor (haplotype2) was used in a curvilinear model, to test for a possible inverted-U trend in affective symptoms according to COMT-related dopamine availability. ResultsWomen had a significant interaction between COMT haplotypes and adolescent emotional problem on affective symptoms at age 53. Post hoc analysis showed a significant positive association between adolescent emotional problems and affective symptoms at age 53 years in the middle dopamine availability group (valA/valB or met/met; β = .11, p = .007). For men, no significant interactions were observed. ConclusionsCombination of the COMT functional haplotype model and inverted-U model may shed light on the effect of dopaminergic regulation on the trajectory of affective symptoms over the life course.

COMT genotype and non-recovery after a whiplash injury in a Northern European population

BackgroundThe COMT (Catechol-O-Methyl Transferase) gene may influence a person’s vulnerability to develop long-term pain and some COMT single nucleotide polymorphisms (SNPs) may associate with patterns of acute or chronic pain. Many patients with whiplash-associated disorders (WADs) suffer from long-term pain and other related symptoms, but it is less known if genetic factors play a role in the recovery process. The primary aim of this study was to evaluate whether self-reported non-recovery, including pain, was related to COMT genotype in patients with WAD. The secondary aim was to investigate whether or not background factors, including mental health, were related to genotype and non-recovery.MethodsA total of 133 patients with neck pain after a whiplash trauma were included. Background factors were collected and blood samples were taken during the acute phase after the accident. DNA was isolated from blood and used to genotype the SNPs rs6269, rs4633, rs4818 and rs4680 in the COMT gene; additionally haplotypes were estimated and haplogenotypes inferred. The patients were followed up after 12 months and asked to rate their recovery including pain, mental health and quality of life.ResultsThe overall reported non-recovery rate at 12 months was 44% with no significant differences in distribution of the COMT haplotypes. High levels of self-reported pain (OR 7.2) and anxiety (OR 4.4) after the accident were associated with non-recovery, but not related to the haplotypes. None of the other background factors were related to the haplotypes or non-recovery.ConclusionNo association between self-reported non-recovery or pain levels and COMT haplotypes in patients with acute whiplash injuries could be detected. Independent replications are necessary to discard the hypothesis that COMT haplotypes do not influence non-recovery or pain levels in patients with acute whiplash injuries. High levels of initial pain and anxiety were associated with non-recovery, thereby confirming previously published reports.

Roles of functional catechol-O-methyltransferase genotypes in Chinese patients with Parkinson\u2019s disease

BackgroundRecent studies have found that the functional catechol-O-methyltransferase (COMT) gene may be associated with the susceptibility to and pharmacotherapy of Parkinson’s disease (PD). In this case–control study, we investigated the most common functional COMT gene haplotypes that had been shown to influence COMT enzymatic activity and the association of the single and combined COMT haplotypes with clinical symptoms and pharmacotherapy in Chinese patients with PD.MethodsOne hundred forty-three patients with idiopathic PD and 157 healthy individuals were enrolled in this study. Four single nucleotide polymorphisms (SNPs) in the COMT gene (formed by SNPs) were genotyped in each participant: rs6269 A > G; rs4633 C > T; rs4818 C > G; and rs4680 G > A.ResultsThe frequencies of rs4633 T carriers, rs4680 A carriers and the two linked rs4633-rs4680 T/A carriers were significantly higher in the early onset PD group than in the healthy controls (all P < 0.05). Homozygosity for rs4633 (TT), rs4680 (AA) and of the two linked rs4633-rs4680 (TT/AA) was significantly more frequent in patients who exhibited the “wearing-off” phenomenon, longer disease duration, higher levodopa equivalent doses (LED) and higher Unified Parkinson’s Disease Rating Scale (UPDRS) scores (P < 0.05). No significant differences were observed in the clinical features of patients who carried individual rs6269 and rs4818, the two linked rs6269-rs4818 and the four combined COMT SNPs.ConclusionsThe results showed a possible association of combined functional COMT SNPs with PD risk, disease duration, the “wearing-off” phenomenon, daily LEDs and higher UPDRS scores, which may be useful in instituting individualized therapy for patients with PD.

Association between cerebrospinal fluid dopamine concentrations and catechol-O-methyltransferase gene polymorphisms in forensic autopsy cases of methamphetamine abusers

Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers.

(476) Assessing pain perception by genetic testing of COMT haplotypes influences clinical decisions for chronic non-cancer pain patients

Researchers have identified candidate genes including catechol-O-methyltransferase (COMT) haplotypes that are associated with pain perception in patients with various chronic non-cancer pain (CNCP) related etiologies. Currently, however, assessment of pain perception is limited to questionnaires and physician interpretation—both of which yield primarily subjective data. Testing for pain perception-related COMT haplotypes provides objective information that may be pertinent to the treatment plan. Hence, the goal of this study was to determine if physicians adjust treatment plans based on genetic tests of pain perception, and whether these treatment changes resulted in better pain relief for patients. A retrospective, cross-sectional study was carried out on 101 CNCP patients. Genotyping for COMT haplotypes was performed using pre-designed TaqMan® single nucleotide polymorphism (SNP) Genotyping Assays (Thermo Fisher Scientific). Genotyping results indicated that 33% of subjects had low pain perception scores; 27% moderate scores; and 23% high scores. Results were not available for 17% of patients. Based on pain perception scores, 23% of physicians adjusted treatment plans. Medication dose changes were made for 6% of patients; further diagnostic testing (electromyography and lumbar puncture) was recommended for 10%; alternative therapy for 7%. Of patients receiving pharmacological interventions, physicians believed 71% of physicians believed patients had a significantly improved or improved response; 14% had no change; and 0% had a worse response. Answers were unavailable for 14% of patients. Thus, although a patient’s pain perception is determined by complex physical, psychological, environmental, cultural, and genetic factors, our results indicate that assessing pain perception via genotyping for COMT haplotypes has a significant effect on clinical decision-making for CNCP patients. In addition, interventions based on objective genetic testing results appeared to improve pain-relief response for these subjects. This study was funded by Proove Biosciences Inc.

Modulative effects of COMT haplotype on age-related associations with brain morphology.

Catechol-O-methyltransferase (COMT), located on chromosome 22q11.2, encodes an enzyme critical for dopamine flux in the prefrontal cortex. Genetic variants of COMT have been suggested to functionally manipulate prefrontal morphology and function in healthy adults. This study aims to investigate modulative roles of individuals COMT SNPs (rs737865, val158met, rs165599) and its haplotypes in age-related brain morphology using an Asian sample with 174 adults aged from 21 to 80 years. We showed an age-related decline in cortical thickness of the dorsal visual pathway, including the left dorsolateral prefrontal cortex, bilateral angular gyrus, right superior frontal cortex, and age-related shape compression in the basal ganglia as a function of the genotypes of the individual COMT SNPs, especially COMT val158met. Using haplotype trend regression analysis, COMT haplotype probabilities were estimated and further revealed an age-related decline in cortical thickness in the default mode network (DMN), including the posterior cingulate, precuneus, supramarginal and paracentral cortex, and the ventral visual system, including the occipital cortex and left inferior temporal cortex, as a function of the COMT haplotype. Our results provided new evidence on an antagonistic pleiotropic effect in COMT, suggesting that genetically programmed neural benefits in early life may have a potential bearing towards neural susceptibility in later life. Hum Brain Mapp 37:2068-2082, 2016. © 2016 Wiley Periodicals, Inc.

Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia

Different genetic variations in the catechol-O-methyltransferase (COMT) gene have been indicated to functionally regulate the encoded enzyme. Despite the vast literature on the single nucleotide COMT ValMet polymorphism, the impact of complex haplotypes on cognitive functions has been overlooked. Here we contrasted the effects of complex COMT haplotypes with the ValMet polymorphism on cognitive functions and their interaction with menopause, in healthy subjects and patients with schizophrenia. Healthy adults (N=229) as well as patients with schizophrenia (N=172) underwent a comprehensive cognitive assessment taking into account the menopausal state. Functional COMT variations selectively modulated working memory and executive functions. Strikingly, these effects were present only in adult men but not in women before menopause, in both healthy subjects and patients with schizophrenia. Importantly, the same pattern of COMT-dependent effects present in men reappeared in women after menopause. Thus, functional COMT mutations seem to modulate cognitive functions depending on the hormonal status. These data clarify the importance of taking into account the combined effect of sex, hormonal status and genetics.

No association of Catechol-O-Methyltransferase (COMT) Gene Haplotypes in Patients with Schizophrenia in a Turkish Sample

Objective: The dopaminergic system, especially variations in the catechol-O-methyltransferase (COMT) gene, is of major interest in the etiology of schizophrenia. The rs4680 (Val108/158Met), rs165599, and P2 promoter rs2075507 single nucleotide polymorphisms (SNPs) in the COMT gene have been shown to be associated with alteration of COMT gene expression and COMT enzyme activity. The aim of this study was to investigate a possible association between schizophrenia and the haplotypes of these polymorphisms.Methods: The sample was comprised of 181 patients with schizophrenia and 368 healthy controls. The patients' psychotic symptoms were rated using the Positive and Negative Symptom Scale (PANSS). COMT rs2075507, rs4680, and rs165599 SNPs were evaluated by a polymerase chain reaction, followed by restriction fragment length polymorphism analysis. These SNPs in the COMT gene were subjected to haplotype analyses using Haploview ver. 4.2.Results: No significant differences were found between COMT rs2075507, rs4680, and rs165599 SNPs in schizophrenic patients and controls. The patients' PANSS results were not associated with these SNPs. No associations were obtained between 2 and 3-haplotypes of rs2075507, rs4680, rs165599 SNPs and schizophrenia.Conclusion: COMT rs2075507, rs4680, rs165599 SNPs and haplotypes do not appear to be risk factors for schizophrenia in this population.

Catechol-O-methyltransferase Val158Met polymorphism: modulation of wearing-off susceptibility in a Chinese cohort of Parkinson's disease.

Catechol-O-methyltransferase (COMT) is one of the cardinal enzymes that metabolize dopamine and other catecholamine neurotransmitters in the central and peripheral nervous system. Recent studies have shown that the impact of COMT haplotypes on the development of wearing-off phenomenon is in dispute, while the relationship between COMT haplotypes and wearing-off phenomenon in ethnic Chinese population is lacking. The purpose of this study was to characterize the correlation between the Val158Met polymorphism in the COMT gene and the motor complication "wearing-off" in Chinese PD patients. We have sequenced the COMT gene in 259 PD patients and 257 healthy controls. Our results demonstrated that Met/Met homozygosity of the COMT Val158Met polymorphism was related to a decreased risk of developing wearing-off. This finding suggests that COMT Val158Met may affect susceptibility to wearing-off in PD.

Genetic Polymorphisms of Catechol-O-Methyltransferase Modify the Neurobehavioral Effects of Mercury in Children

Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8–12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene–Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: a report on 176 cases

BackgroundThis study was aimed at the evaluation of the relationship between genetic polymorphisms of catechol-O-methyltransferase (COMT) (rs4680:A > G—Val158Met, rs6269:A > G, rs4633:C > T, rs4818:C > G) and pain sensitivity after lumbar discectomy.MethodsAll patients had one-level symptomatic disc herniation from L3 to S1. The primary data recorded included visual analogue pain scales assessing back and leg pain, Oswestry Disability Questionnaire assessing quality of life and pain intensity, received/filled pre- and postoperatively. Each subject was genotyped for single-nucleotide polymorphism in the COMT gene. Clinical outcome was measured by difference between pre- and postoperative values and those results were analyzed with genetics findings.ResultsPain intensity was associated with the COMT polymorphism. Carriers of rs6269 AA, rs4633 TT, rs4818 CC, and rs4680 AA genotypes were characterized by the lowest preoperative scores related to pain intensity and lower pain intensity at 1 year after the surgery. The rs4633 CC, rs4680 GG genotypes demonstrated significant clinical improvement in VASBACK score at 1 year after the surgery. Patients with COMT haplotype associated with low metabolic activity of enzyme (A_C_C_G) showed better clinical outcome measured by ODI score and VASBACK score 1 year after surgery. We did not observe any significant correlation between leg pain and single-nucleotide polymorphisms in the COMT gene.ConclusionsThe results of our study indicate that polymorphism in the COMT gene may play an important role in the mechanism of pain perception, which may have a potential implication for clinical decision-making in the future.

Schooling and variation in the COMT gene: the devil is in the details

Schooling is considered one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. We studied a sample of 1,502 children (mean age = 11.7 years) from Zambia. Approximately 57% of these children were enrolled in school, and the rest were not. To quantify genetic variation, we investigated a number of common polymorphisms in the catechol-O-methyltransferase (COMT) gene that controls the production of the protein thought to account for >60% of the dopamine degradation in the prefrontal cortex. Haplotype analyses generated results ranging from the presence to absence of significant interactions between a number of COMT haplotypes and indicators of schooling (i.e., in- vs. out-of-school and grade completed) in the prediction of nonverbal intelligence, depending on the parameter specification. However, an investigation of the distribution of corresponding p-values suggested that these positive results were false. Convincing evidence that the variation in the COMT gene is associated with individual differences in nonverbal intelligence either directly or through interactions with schooling was not found. p-values produced by the method of testing for haplotype effects employed here may be sensitive to parameter settings, invalid under default settings, and should be checked for validity through simulation.

The lack of association between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and schizophrenia in a group of Turkish population

IntroductionSchizophrenia is a complex neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotions. Family and twin studies have provided cumulative evidence for the genetic basis of schizophrenia. The aetiolgy of this disease involves the interplay of multifactiorial inheritance operating on brain maturational processes and polygenic inheritance with some genes showing susceptibility at many genomic locations such as 22q and 11q.The catechol-O-methyltransferase (COMT-22q11) is an extensively studied candidate gene for schizophrenia. COMT acts as an enzymatic detoxicating barrier between the blood and other tissues regulating the amounts of active dopamine and norepinephrine in various parts of the brain and therefore to be associated with schizophrenia.The presence of a common functional single nucleotide polymorphism (SNP) in exon 4 [Guanine (G) Adenine (A); Val108/158Met], alters the enzymatic activity with a trimodal distribution of high-HH, intermediate-HL and low-LL activity alleles which appear to have association with schizophrenia.Brain-derived neurotrophic factor (BDNF-11q13) is a member of the nerve growth factor family working as a molecular regulator of neuronal development and plasticity. Molecules that are critical in the development and survival of neurons such as BDNF play a significant role in the neuropathology of schizophrenia. While upregulation of BDNF increases the neuronal cell size and synaptic plasticity, a functional polymorphism at codon 66 [G→A; Val66Met] down regulates this process and induces schizophrenia. ObjectiveIn the present study, our aim was to investigate the differences in allele frequencies between schizophrenic patients [n=97 (51 men, 46 women)] and control group [n=376 (228 men, 148 women)] subjects. ResultsWhen the control and schizophrenia groups were compared for BDNFVal66Met polymorphism, we did not find a significant difference between the study groups either for genotype (χ2=3.370447, p>0.05) or Val/Met haplotype analysis (χ2=2.840264, p>0.05). When a comparison was revealed for COMT-Val108/158Met polymorphism, no significant difference was detected among schizophrenia and control groups for genotype (χ2=0.373330, p>0.05) and Val/Met haplotype analysis (χ2=0.339073, p>0.05). When the control and study groups were compared for BDNFVal66Met–COMTVal108/158Met polymorphisms compound genotype and haplotype analyses, there was no significant difference between the two groups (χ2=11.015; p>0.05 and χ2=3.191; p>0.05), respectively. ConclusionOur results indicate that there is no association between schizophrenia and BDNF–COMT polymorphisms and haplotypes analysis. We also did not find an association between schizophrenia and BDNF–COMT compound genotype and haplotype analyses. Although our study is unique in Turkey as combining BDNF and COMT compound genotype–haplotype analyses, for a generalization of Turkish schizophrenia patient's susceptibility to schizophrenia; we need further studies with an enlarged cohort.