Showing papers on "Catechol-O-methyl transferase published in 2017"

TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.

Abstract: ObjectivesCisplatin ototoxicity affects 42–88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to inves

The catechol-O-methyltransferase ( COMT ) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder

Abstract: Objectives Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD Methods Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]) The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner Results During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=016) Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤006), with deficits being most pronounced in Val homozygotes Conclusions The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

Abstract: Introduction: Previous research has indicated that variation in genes encoding catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) may influence cognitive function and that this may confer vulnerability to the development of mental health disorders such as schizophrenia. However, increasing evidence suggests environmental factors such as early life stress may interact with genetic variants in affecting these cognitive outcomes. This study investigated the effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress in healthy adults. Methods: One hundred and twenty-two healthy adult males (mean age 35.2 years, range 21–63) were enrolled in the study. Cognitive function was assessed using Cambridge Neuropsychological Test Automated Battery and early life stress was assessed using the Childhood Traumatic Events Scale (Pennebaker & Susman, 1988). Results: DRD2 C957T was significantly associated with executive function, with CC homozygotes having significantly reduced performance in spatial working memory and spatial planning. A significant genotype–trauma interaction was found in Rapid Visual Information Processing test, a measure of sustained attention, with CC carriers who had experienced early life stress exhibiting impaired performance compared to the CC carriers without early life stressful experiences. There were no significant findings for COMT Val158Met. Conclusions: This study supports previous findings that DRD2 C957T significantly affects performance on executive function related tasks in healthy individuals and shows for the first time that some of these effects may be mediated through the impact of childhood traumatic events. Future work should aim to clarify further the effect of stress on neuronal systems that are known to be vulnerable in mental health disorders and more specifically what the impact of this might be on cognitive function.

Depression and Catechol-O-methyltransferase (COMT) genetic variants are associated with pain in Parkinson's disease.

Abstract: Pain is a distressing symptom of Parkinson disease (PD). We aim to determine whether the genetic variants of chronic pain-related genes contribute to pain in PD patients. We included 418 PD patients and evaluated pain severity on King’s PD pain scale. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of COMT, rs6746030 of SCN9A, and rs1799971 of OPRM1. In total, 193 participants (46.2%) experienced pain. Compared to pain-free PD patients, PD patients with pain had an earlier age of onset, longer disease duration, and higher depression and motor severity (P < 0.01). The frequencies of COMT rs4680 “A” allele were higher in PD patients with pain than those without pain (46.1% vs. 31.1%, P < 0.01). Pain severity was significantly associated with disease duration (P = 0.02), and COMT rs6267 T allele (P < 0.01). We stratified PD by status of depression and the association between COMT rs6267 “GT” genotype and pain severity remained significant (P < 0.01). Furthermore, pain severity was significantly higher in participants having COMT rs4680 “GG” and “GA” genpotypes than those having “AA” genotype (P = 0.04). We concluded that depression and COMT rs4680 “GG” and “GA” genotypes and COMT rs6267 “GT” genotype contribute to pain in PD patients.

Catechol-O-Methyltransferase (COMT): An Update on Its Role in Cancer, Neurological and Cardiovascular Diseases.

Abstract: Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the methylation of catechol substrates, classically in catecholamine metabolism, but also acting upon other substrates such as oestrogen and polyphenols. Although its classical function has been established for more than five decades, an ever expanding COMT role in other pathways and diseases has become a subject of active study in recent years. The most highlighted domains are related with COMT involvement in neuropsychiatric disorders and its role in the neurobiology of cognition, behaviour, emotions, pain processing and perception, sleep regulation, addictive behaviour and neurodegeneration. Nonetheless, great attention is also being devoted to a possible COMT contribution to the development of cardiovascular disorders and hormonally influenced diseases, including cancer. This review aims to update the role of COMT function and its involvement in cardiovascular and neurological disorders.

An Optimized Two-Photon Fluorescent Probe for Biological Sensing and Imaging of Catechol-O-Methyltransferase

Abstract: A practical two-photon fluorescent probe was developed for highly sensitive and selective sensing of the activities of catechol-O-methyltransferase (COMT) in complex biological samples To this end, a series of 3-substituted 7,8-dihydroxycoumarins were designed and synthesized Among them, 3-BTD displayed the best combination of selectivity, sensitivity, reactivity, and fluorescence response following COMT-catalyzed 8-O-methylation The newly developed two-photon fluorescent probe 3-BTD can be used for determining the activities of COMT in complex biological samples and bio-imaging of endogenous COMT in living cells and tissue slices with good cell permeability, low cytotoxicity, and high imaging resolution All these findings suggest that 3-BTD holds great promise for developing therapeutic molecules that target COMT, as well as for exploring COMT-associated biological processes and its biological functions in living systems Furthermore, the strategy also sheds new light on the development of fluorescent probes for other conjugative enzymes

Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice.

Abstract: 2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o-methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient-associated metabolic defects. Liver COMT protein was suppressed in high fat diet (HFD)-fed or in pregnant mice. COMT suppression, by Ro41-0960 or siRNA, in HFD fed mice or in pregnant mice exacerbated glucose intolerance; 2-ME intervention ameliorated these defects. 2-ME effects on glucose tolerance were associated with AMPK phosphorylation in the liver and in islet cells. Metformin restored liver COMT protein levels, and metformin-induced liver AMPK phosphorylation was abolished by COMT inhibition. The amelioration in glucose tolerance by 2-ME was associated with biphasic insulin secretion in an environment-dependent manner. 2-ME-induced insulin secretion was associated with the AMPK phosphorylation, PDX-1 phosphorylation, and MST-1 suppression in MIN-6 cells. Furthermore 2-ME displayed PPARγ agonist-like activity. These results suggest that COMT is an enzyme to maintain glucose homeostasis and 2-ME is a potential endogenous multi-target anti-diabetic candidate.

Adolescence is the starting point of sex-dichotomous COMT genetic effects

Abstract: The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects Some of these effects may vary among sexes However, the developmental trajectories of COMT-by-sex interactions are unclear Here we found that extreme COMT reduction, in both humans (22q112 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty These biochemical differences were absent in infancy Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex-dichotomous effects in executive functions were already apparent in adolescence These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage

Stressful life events and Catechol-O-methyl-transferase (COMT) gene in bipolar disorder

Abstract: Background: A small body of research suggests that gene-environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the COMT Val158Met polymorphism in bipolar disorder. Methods: A total of 482 bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT Val158Met variant (rs4680) was extracted from GWAS analysis of the sample. Results: The impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted Risk Difference = 0.09, 95% confidence intervals 0.003-0.18, p=0.04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected. Conclusions: This is the first study to explore the relationship between stressful life events and the COMT Val158Met polymorphism focusing solely on bipolar disorder. The results of this study highlight the importance of the interplay between genetic and environmental factors for bipolar depression.

Catechol-O-Methyltransferase Deficiency Leads to Hypersensitivity of the Pressor Response Against Angiotensin II.

Abstract: Catechol-O-methyltransferase (COMT) metabolizes 2-hydroxyestradiol into 2-methoxyestradiol (2-ME); COMT deficiency has shown to be associated with hypertension in men and preeclampsia, the disease associated with hypersensitivity of pressor response against angiotensin II (Ang II). Here, we found that COMT deficiency could explain the hypersensitivity of pressor response against Ang II in mice because of the lack of 2-ME-dependent suppression of angiotensin II receptor type 1 (AT1R). Male C57BL/6 mice were subjected to COMT inhibitor (COMTi: 25 mg/kg per day) or oil (control) for 4 weeks, with or without low-dose Ang II infusion (ANGII: 70 ng/kg per minute) for the last 3 weeks. The Ang II-infused mice were treated with 2-ME (10 ng/d) or vehicle for the last 1 week. We obtained the following experimental groups: control, ANGII, COMTi, COMTi+ANGII, and COMTi+ANGII+2-ME. We performed similar experiments using the in vivo administration of small interfering RNA of COMT instead of COMTi. Neither ANGII nor COMTi exhibited significant alterations in systolic blood pressure. Compared with ANGII or COMTi, COMTi+ANGII displayed significantly higher systolic blood pressure, albuminuria, and glomerular endotheliosis; 2-ME normalized such alterations. Similar phenotypes were observed in COMT small interfering RNA-treated mice. In the aorta of COMT-deficient mice, AT1R expression was increased; 2-ME suppressed AT1R expression. The 2-ME exhibited peroxisome proliferator-activated receptor γ agonistic activity in vitro and ex vivo plasma from pregnant female mice as well. In vitro, 2-ME suppressed both basal and Ang II-induced AT1R levels in a peroxisome proliferator-activated receptor γ-dependent manner. The 2-ME is relevant to combat COMT deficiency-associated hypertensive disorders via suppression of AT1R by its peroxisome proliferator-activated receptor γ activity.

Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia.

Abstract: BACKGROUND Cognitive deficits such as poor selective attention and executive functions decline have been reported in patients with schizophrenia. Many studies have emphasized the role of dopamine in regulating cognitive functions in the general population as well as in schizophrenia. However, the relationship between cognitive processes, schizophrenia and dopaminergic candidate genes is an original approach given interesting results. The purpose of the current exploratory study was to examine the interaction of dopaminergic genes (coding for dopamine receptor D2, DRD2, and for Catecholamine-O-Methyl-Transferase, COMT) with the diagnostic of schizophrenia in (i) the executive control of attention, (ii) selective attention, and (iii) executive functions. METHODS AND RESULTS We recruited 52 patients with schizophrenia and 53 healthy controls who performed the Stroop Color-Word Test, the Attention Network Test and the Wisconsin Card Sorting test. Four single nucleotide polymorphisms (SNPs) in the DRD2 gene (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599) have been genotyped. Patients with schizophrenia performed significantly worse than controls in all cognitive performance, taking into account demographic variables. A significant gene by disease interaction was found for the Stroop interference (p = 0.002) for rs6275 of the DRD2 gene. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors (p = 0.01). CONCLUSIONS In our study, the DRD2 gene is involved in attention while the COMT gene is implicated in executive functions in patients with schizophrenia.

Catechol-O-methyltransferase, Cognition and Alzheimer's Disease.

Abstract: Objective Cognition is a complex trait representing a set of all mental abilities and processes related to knowledge. Although diverse brain regions are involved, most cognitive processes appear to engage cortical regions. The activity of dopaminergic neurons in prefrontal cortex represents a biological substrate underlying cognitive functions. Alzheimer's Disease (AD) is the most frequent dementia associated with cognitive impairments. Cognitive impairment in AD starts slowly with discrete deterioration in memory, language, thinking and reasoning, but it progresses into more severe and debilitating cognitive dysfunction. Cognitive function is affected by the complex interactions between various genetic, epigenetic, developmental and environmental factors. One of the most studied genes, associated with cognitive disturbances, is the gene coding for Catechol-O-methyltransferase (COMT), the enzyme with major role in dopamine metabolism and modulation of different brain functions. Therefore, COMT is studied as a target for many neuropsychiatric disorders, including dementias and AD. The COMT Val158/108Met functional polymorphism affects significantly the enzyme activity and consequently cognitive performance associated with altered dopamine function. The association of COMT Val158/108Met polymorphism with some cognitive domains and psychosis in AD was reported in some but not in all studies. Besides COMT Val158/108Met polymorphism, other risk genotypes or haplotypes should be evaluated to determine the association of COMT with cognitive decline in AD. Conclusion Better understanding of the role of COMT in cognitive processes in AD, as well as integration of neurobiological, genetic, genomic and epigenetic data, might help in developing new potential therapies of cognitive impairments and psychotic symptoms, characteristic features of AD.

Impact of Catechol-O-Methyltransferase Val 158Met (rs4680) Polymorphism on Breast Cancer Susceptibility in Asian Population

Abstract: Background: Catechol-O-methyltransferase (COMT) is an important estrogen-metabolizing enzyme. Numerous case-control studies have evaluated the role COMT Val 158Met (rs4680;472G->A) polymorphism in the risk of breast cancer and provided inconclusive results, hence present meta-analysis was designed to get a more reliable assessment in Asian population. Methods: A total of 26 articles were identified through a search of four electronic databases- PubMed, Google Scholar, Science Direct and Springer link, up to March, 2016. Pooled odds ratios (ORs) with 95% con¬fidence intervals (CIs) were used as association measure to find out relationship between COMT Val158Metpolymorphism and the risk of breast cancer. We also assessed between study heterogeneity and publication bias. All statistical analyses were done by Open Meta-Analyst. Results: Twenty six case-control studies involving 5,971 breast cancer patients and 7,253 controls were included in the present meta-analysis. The results showed that the COMT Val158Met polymorphism was significantly associated with breast cancer risk except heterozygote model(allele contrast odds ratio (ORAvsG)= 1.13, 95%CI=1.02-1.24,p=0.01; heterozygote/co-dominant ORGAvsGG= 1.03, 95%CI=0.96-1.11,p=0.34; homozygote ORAAvsGG= 1.38, 95%CI= 1.08-1.76,p=0.009; dominant model ORAA+GAvsGG= 1.08, 95%CI=1.01-1.16,p=0.02; and recessive model ORAAvsGA+GG= 1.35, 95%CI=1.07-1.71,p=0.01). In addition, we also performed subgroup analysis based on source of controls and menopausal state of patients. Conclusions: In conclusion, the COMT Val158Met polymorphism was related to increased breast cancer susceptibility in the Asian population.

The Val158Met polymorphism in COMT gene and cancer risk: role of endogenous and exogenous catechols.

Abstract: Catechol-O-methyltransferase, COMT, is an important phase II enzyme catalyzing the transfer of a methyl-group from S-adenosylmethionine to a catechol-containing substrate molecule. A genetic variant Val158Met in the COMT gene leads to a several-fold decrease in the enzymatic activity giving rise to the accumulation of potentially carcinogenic endogenous catechol estrogens and their reactive intermediates and increasing thus the risk of tumorigenesis. However, numerous association studies between the COMT genotype and susceptibility to various malignancies have shown inconsistent and controversial findings indicating that additional gene-gene and gene-environment interactions might be crucial in modulating the physiological role of the COMT. In this review article, the important contribution of dietary catechol-containing flavonoids to modification of the relationships between the COMT genotype and cancer risk is discussed. Whereas, the diverse anticancer activities of common phytochemicals, such as green tea polyphenols, quercetin, fisetin or luteolin, can be markedly changed (both decreased or increased) by the COMT-mediated O-methylation of these exogenous substrates, flavonoids can also behave as potent inhibitors of the COMT enzyme slowing detoxification of endogenous catechol estrogens. Such a many-featured functioning of the COMT and its complex regulation by several different genetic and environmental factors, including plant-based food ingredients, emphasizes the necessity to further stratify the association studies between the COMT genotype and tumor risk by consumption of catechol-containing dietary flavonoids. Currently, it can be only speculated that some of the possible associations might be masked by the regular intake of specific food polyphenols, taking effect in certain communities or populations.

Association between Catechol-O-Methyltransferase Val158Met (158G/A) Polymorphism and Suicide Susceptibility: A Meta-analysis.

Abstract: Background: Common functional Val158Met polymorphism in the Catechol-O-methyltransferase (COMT) gene may have an impact on an individual’s susceptibility to suicide, but individually published results are inconclusive. Therefore, we performed this meta-analysis to provide a more precise estimation of the association between COMT 158G/A (COMT Val158Met) polymorphism and suicide susceptibility. Study design: A cross-sectional study. Methods: This systematic review and meta-analysis is a comprehensive literature search of PubMed, Scopus, Web of Science and Google Scholar databases was conducted on case-control studies published up to Mar 2017. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: We identified 14 eligible case-control studies, including 2353 suicide attempters and 2593 controls. The pooled results indicated that COMT 158G/A (COMT Val158Met) polymorphism was not significantly associated with increased overall suicide risk. The same results were revealed based on ethnicity, Hardy–Weinberg equilibrium (HWE) status and genotyping technique. However, there was significant association between COMT Val158Met polymorphism and suicide risk among females under the homozygote (AA vs. GG: OR=1.829, 95% CI=1.158-2.889, P =0.010) and recessive (AA vs. AG +GG: OR = 1.787, 95% CI=1.195, 2.671, P =0.005) models, but not among males. Conclusions: COMT 158G/A (COMT Val158Met) polymorphism was associated with suicide susceptibility only in females.

Age-Dependent Effects of Catechol-O-Methyltransferase (COMT) Gene Val158Met Polymorphism on Language Function in Developing Children

Abstract: The genetic basis controlling language development remains elusive. Previous studies of the catechol-O-methyltransferase (COMT) Val158Met genotype and cognition have focused on prefrontally guided executive functions involving dopamine. However, COMT may further influence posterior cortical regions implicated in language perception. We investigated whether COMT influences language ability and cortical language processing involving the posterior language regions in 246 children aged 6-10 years. We assessed language ability using a language test and cortical responses recorded during language processing using a word repetition task and functional near-infrared spectroscopy. The COMT genotype had significant effects on language performance and processing. Importantly, Met carriers outperformed Val homozygotes in language ability during the early elementary school years (6-8 years), whereas Val homozygotes exhibited significant language development during the later elementary school years. Both genotype groups exhibited equal language performance at approximately 10 years of age. Val homozygotes exhibited significantly less cortical activation compared with Met carriers during word processing, particularly at older ages. These findings regarding dopamine transmission efficacy may be explained by a hypothetical inverted U-shaped curve. Our findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change in a narrow age window of 6-10 years.

Prospective replication study implicates the catechol-O-methyltransferase Val158Met polymorphism as a biomarker for the response to morphine in patients with cancer.

Abstract: Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680; p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naive patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naive and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.

Potential link between genetic polymorphisms of catechol-O-methyltransferase and dopamine receptors and treatment efficacy of risperidone on schizophrenia

Abstract: Objective The current study aimed to explore the association of single nucleotide polymorphisms (SNPs) within catechol-O-methyltransferase (COMT) and dopamine receptors with schizophrenia and genetic association with risperidone treatment response. Methods A total of 690 schizophrenic patients (case group) were selected and 430 healthy people were included as the controls. All patients received risperidone treatment continuously for 8 weeks. Next, peripheral venous blood samples were collected and were subjected to polymerase chain reaction-restriction fragment length polymorphism to amplify and genotype the SNPs within COMT and dopamine receptors. Then, correlation analysis was conducted between Positive and Negative Syndrome Scale improvement rates and SNPs within COMT and the dopamine receptor gene. Results The allele of DRD1 rs11749676 (A) emerged as a key element in reducing schizophrenia risk with statistical significance (P<0.001). Remarkably, alleles of COMT rs165774 (G), DRD2 rs6277 (T), and DRD3 rs6280 (C) were associated with raised predisposition to schizophrenia (all P<0.001). Regarding DRD1 rs11746641, DRD1 rs11749676, DRD2 rs6277, and DRD3 rs6280, the case group exhibited a lesser frequency of heterozygotes in comparison with wild homozygotes genotype (all P<0.001). SNPs (COMT rs4680, DRD2 rs6275, DRD2 rs1801028, and DRD2 rs6277) were remarkably associated with improvement rates of PANSS total scores (P<0.05). SNPs (COMT rs165599 and DRD2 rs1801028) were significantly associated with risperidone efficacy on negative symptoms (P<0.05). Conclusion COMT SNPs and dopamine receptor SNPs were correlated with prevalence of schizophrenia and risperidone treatment efficacy of schizophrenia.

Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites.

Abstract: 1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has...

Aberrant endometrial DNA methylome of homeobox A10 and catechol-O-methyltransferase in endometriosis.

Abstract: Differential methylation of both HOXA10 and catechol-O-methyltransferase (COMT) has been reported in different endometrium disorders, and the two genes are linked through the estrogen pathway. The current study investigates the DNA methylation of HOXA10 and COMT in ectopic and eutopic endometrial tissues and its correlation with and the occurrence of endometriosis in women from Xinjiang province in China. In the current study, 120 patients with endometriosis were recruited from our hospital between January 2011 and June 2014. The DNA methylation sites of HOXA10 and COMT were detected using a DNA methylation array. The methylation levels of specific sites were compared between ectopic and eutopic endometrial tissues via pyrosequencing. Five differentially expressed CpGs were localized in the promoter region of the COMT gene and expressed significantly higher in the ectopic endometrium than the eutopic endometrium (P < 0.001). Two out of the five differentially expressed CpGs in the HOXA10 gene located in the promoter region were both significantly lower (nearly half) in the ectopic endometrium than the eutopic endometrium (P < 0.001). To summarize, significant differential methylation of HOXA10 and COMT promoter regions was found between the ectopic and eutopic endometrial tissues. This is the first study investigating the methylation of HOXA10 and COMT genes and their linkage to endometriosis in Chinese patients.

COMT and BDNF Gene Variants Help to Predict Alcohol Consumption in Alcohol-dependent Patients.

Abstract: Background The neurobiology of alcohol dependence (AD) involves alterations in neurotransmitters and the stress response. We hypothesized that an interaction between functional variants of dopaminergic and neurotrophic genes may influence drinking in AD. Methods The relationship between alcohol consumption and single-nucleotide polymorphisms, Val66Met in the brain-derived neurotrophic factor (BDNF), and Val158Met in the catechol-O-methyltransferase (COMT), was analyzed among 281 alcohol-dependent individuals. Results Individuals carrying both the COMT Met158Met genotype and the BDNF Val66Val genotype drank more than those with other variants of these genes (P = 0.039). Those who had a family history of AD also drank more than those without a family history (P = 0.048). Patients with both Met/Met genotype in the COMT Val158Met polymorphism and Val/Val genotype in the BDNF Val66Met polymorphism suffered from more health problems than those carrying other variants (P = 0.030) and had lower motivation to change drinking patterns (P = 0.031). Conclusions Patients carrying both the BDNF Val66Val and COMT Met158Met variants had higher alcohol consumption. These effects may be influenced by the effects of BDNF and COMT on dopamine responses to alcohol. Motivation-enhancing strategies might benefit the group of patients identified by genotyping in this study, and also treatment aimed at reducing alcohol consumption.

Green tea extract and catechol-O-methyltransferase genotype modify the post-prandial serum insulin response in a randomised trial of overweight and obese post-menopausal women.

Abstract: BACKGROUND: Green tea extract (GTE) may be involved in a favourable post‐prandial response to high‐carbohydrate meals. The catechol‐O‐methyltransferase (COMT) genotype may modify these effects. We examined the acute effects of GTE supplementation on the post‐prandial response to a high‐carbohydrate meal by assessing appetite‐associated hormones and glucose homeostasis marker concentrations in women who consumed 843 mg of (−)‐epigallocatechin‐3‐gallate (EGCG) or placebo capsules for 11–12 months. METHODS: Sixty Caucasian post‐menopausal women (body mass index ≥ 25.0 kg m–²) were included in a randomised, double‐blind feeding study. GTE was consumed with a breakfast meal [2784.0 kJ (665.4 kcal); 67.2% carbohydrate]. Blood samples were drawn pre‐meal, post‐meal, and every 30 min for 4 h. Participants completed six satiety questionnaires. RESULTS: Plasma leptin, ghrelin and adiponectin did not differ between GTE and placebo at any time point; COMT genotype did not modify these results. Participants randomised to GTE with the high‐activity form of COMT (GTE‐high COMT) had higher insulin concentrations at time 0, 0.5 and 1.0 h post‐meal compared to all COMT groups randomised to placebo. Insulin remained higher in the GTE‐high COMT group at 1.5, 2.0 and 2.5 h compared to Placebo‐low COMT (P < 0.02). GTE‐high COMT had higher insulin concentrations at times 0, 0.5, 1.0, 1.5 and 2.0 h compared to the GTE‐low COMT (P ≤ 0.04). Area under the curve measurements of satiety did not differ between GTE and placebo. CONCLUSIONS: GTE supplementation and COMT genotype did not alter acute post‐prandial responses of leptin, ghrelin, adiponectin or satiety, although it may be involved in post‐meal insulinaemic response of overweight and obese post‐menopausal women.

Roles of functional catechol-O-methyltransferase genotypes in Chinese patients with Parkinson's disease.

Abstract: Recent 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. One 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. The 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. The 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.