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1.
Gene ; 781: 145538, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33631245

RESUMO

BACKGROUND: The genetics of binge-eating disorder (BED) is an emerging topic, with dopaminergic genes being implicated in its etiology due to the role that dopamine (DA) plays in food reward sensitivity and self-regulation of eating behavior. However, no study to date has examined if DA genes influence response to behavioral treatment of BED. OBJECTIVE: The primary objective of this study was to examine the ability of DA-associated polymorphisms to predict BED treatment response measured using binge frequency over 12 months. As secondary objectives, this study examined cross-sectional relationships between these polymorphisms and anthropometrics in women living with and without BED and obesity. METHODS: Women aged 18-64 years old were genotyped for the DA-related SNPs DRD2/ANKK1 Taq1A (rs1800497) and COMT (rs4680), as well as the DA-related uVNTRs DAT-1 (SLC6A3) and MAO-A. A multi-locus DA composite score was formed from these 4 polymorphisms using genotypes known to have a functional impact resulting in modified DA signaling. Binge frequency (Eating Disorder Examination - Interview) and body composition (Tanita BC-418) were assessed in a pre-post analysis to examine genetic predictors of treatment response in women living with obesity and BED. Secondary data analysis was conducted on a cross-sectional comparison of three groups of women enrolled in trial group treatment for BED: women living with obesity and BED (n = 72), obesity without BED (n = 27), and normal-weight without BED (n = 45). RESULTS: There were no significant genotype × time interactions related to anthropometrics or binge frequency for any individual DA genotypes, or to the composite score reflecting DA availability. At baseline, there were no significant between-group differences in frequencies of DA-related alleles, nor were there associations between genotypes and anthropometrics. CONCLUSIONS: Our study found no evidence to suggest that the DRD2/ANKK1 Taq1A, COMT, MAO-A, or DAT-1 polymorphisms are associated with response to behavioral intervention for BED as measured by changes in binge frequency. Future studies should examine a greater variety of dopaminergic polymorphisms, other candidate genes that target other neurotransmitter systems, as well as examine their impact on both behavioral and pharmacological-based treatment for BED.


Assuntos
Transtorno da Compulsão Alimentar/genética , Dopamina/genética , Polimorfismo Genético , Adolescente , Adulto , Transtorno da Compulsão Alimentar/metabolismo , Catecol O-Metiltransferase/genética , Estudos Transversais , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Monoaminoxidase/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto Jovem
2.
Gene ; 765: 145107, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32889058

RESUMO

AIM: The Lithuanian population has outstanding rates of alcohol consumption and alcohol related mortality. Alteration of brain dopaminergic system play a role in the risk for addiction disorders. We evaluated the association of one single nucleotide polymorphism rs1800497 in the Ankyrin Repeat and Kinase Domain Containing 1 - Dopamine Receptor D2 complex (ANKK1-DRD2) and a catechol-o-methyltransferase (COMT) rs4680 single nucleotide polymorphism with the risk for alcohol use disorder and impulsiveness in Lithuanian population. Both genetic polymorphisms are known to alter brain dopaminergic activity, thus we also investigated the possible interaction effect of these polymorphisms. METHODS: The study included 329 participants recruited from the local community. Hazardous alcohol use was evaluated using the Alcohol Use Disorder Identification Test (AUDIT). Impulsiveness was measured using the Barratt Impulsiveness Scale - 11 (BIS-11). Between group differences of AUDIT and BIS-11 scores were examined stratified by genetic polymorphisms and their combinations. The independent effect of each polymorphism and their interaction for hazardous alcohol use were evaluated using adjusted logistic regression analyses. RESULTS: The ANKK1-DRD2 rs1800497 polymorphism was associated with total AUDIT score, but not with the hazardous use of alcohol, as indicated by the AUDIT test cut-off of 8. The COMT rs4680 GG genotype was associated with the hazardous use of alcohol (adjusted OR = 2.094, p = 0.029), but this association was not statistically significant after adjustment for multiple comparisons. Presence of both COMT rs4680 and ANKK1-DRD2 rs1800497 GGxCT/TT polymorphisms was associated with significantly increased risk for hazardous use of alcohol (adjusted OR = 5.016, p = 0.005). The COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms, and their combination were not associated with impulsiveness. CONCLUSIONS: Our study demonstrated that the interaction of COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms is associated with a hazardous use of alcohol.


Assuntos
Alcoolismo/genética , Catecol O-Metiltransferase/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto , Alcoolismo/epidemiologia , Alelos , Repetição de Anquirina/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Dopamina D2/metabolismo , Fatores de Risco
3.
Am J Physiol Heart Circ Physiol ; 320(2): H854-H866, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337964

RESUMO

The prevalence of cardiovascular diseases dramatically increases with age; therefore, striving to maintain a physiological heart function is particularly important. Our aim was to study the voluntary exercise-evoked cardioprotective effects in aged male and female rats, from genetic alterations to changes in heart performance. We divided 20-month-old female and male Wistar rats to control and running groups. After the 12-wk-long experimental period, echocardiographic measurements were performed. Afterwards, hearts were either removed for biochemical measurements or mounted into a Langendorff-perfusion system to detect infarct size. The following genes and their proteins were analyzed from heart: catechol-O-methyltransferase (Comt), endothelin-1 (Esm1), Purkinje cell protein-4 (Pcp4), and osteoglycin (Ogn). Recreational exercise caused functional improvements; however, changes were more prominent in males. Cardiac expression of Comt and Ogn was reduced as a result of exercise in aged males, whereas Pcp4 and Esm1 showed a marked overexpression, along with a markedly improved diastolic function. The key result of this study is that exercise enhanced the expression of the Pcp4 gene and protein, a recently described regulator of calcium balance in cardiomyocytes, and suppressed Comt and Ogn gene expression, which has been associated with impaired cardiac function. In addition, as a result of exercise, a significant improvement was observed in the size of infarct elicited by left anterior descending coronary artery occlusion. Our results clearly show that age and sex-dependent changes were both apparent in key proteins linked to cardiovascular physiology. Exercise-moderated fundamental genetic alterations may have contributed to the functional adaptation of the heart.NEW & NOTEWORTHY Voluntary exercise has proved to be an effective therapeutic tool to improve cardiac function in aged rats with clearly visible sex differences. Long-term exercise is associated with decreased Ogn and Comt expression and enhanced presence of Pcp4 and Esm1 genes. Sex-dependent changes were also observed in the expression of the cardiovascular key proteins. Fundamental alterations in gene and protein expression may contribute to the improvement of cardiac performance.


Assuntos
Envelhecimento , Regulação da Expressão Gênica , Coração/fisiologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Condicionamento Físico Animal , Corrida , Adaptação Fisiológica , Animais , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Modelos Animais de Doenças , Feminino , Coração/diagnóstico por imagem , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Preparação de Coração Isolado , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteoglicanas/genética , Proteoglicanas/metabolismo , Ratos Wistar , Fatores Sexuais
4.
Artigo em Russo | MEDLINE | ID: mdl-32790988

RESUMO

A systematic review of association studies on the role of single nucleotide variants (SNVs) of the dopaminergic system genes on the effectiveness of clozapine in schizophrenia has been perfromed. A search of literature was conducted in PubMed, MedLine, Web of Science Core Collection (Clarivate Analytics), Web of Science, Russian Science Citation Index, Scopus, Scientific Research, Google Scholar, Oxford Press, e-Library from 1995-2019. Association studies of 53 SNPs of genes encoding dopamine receptor isoforms (DRD1), dopamine transporter (SCL6A3) and catechol-O- methyltransferase (COMT), and the nature of their association with the therapeutic response to clozapine were analyzed. The results of SNPs studies of DRD1 and COMT genes are the most controversial. This can be explained by the heterogeneity of the samples and the lack of standardization of methods for evaluating the effectiveness of treatment in the context of association studies. The clear population specificity of the association of some SNPs of DRD1, DRD2 and DRD3 genes with the response to clozapine therapy has been shown. Most of the identified associations are haplotype specific. The obtained regularities of the effect of SNPs of dopaminergic system genes on the effectiveness of clozapine therapy should be considered in an individual approach to treatment of schizophrenia.


Assuntos
Clozapina , Esquizofrenia , Catecol O-Metiltransferase/genética , Dopamina , Genótipo , Humanos , Farmacogenética , Polimorfismo de Nucleotídeo Único , Federação Russa
5.
Proc Natl Acad Sci U S A ; 117(20): 10797-10805, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32371482

RESUMO

Human catechol O-methyltransferase (COMT) has emerged as a model for understanding enzyme-catalyzed methyl transfer from S-adenosylmethionine (AdoMet) to small-molecule catecholate acceptors. Mutation of a single residue (tyrosine 68) behind the methyl-bearing sulfonium of AdoMet was previously shown to impair COMT activity by interfering with methyl donor-acceptor compaction within the activated ground state of the wild type enzyme [J. Zhang, H. J. Kulik, T. J. Martinez, J. P. Klinman, Proc. Natl. Acad. Sci. U.S.A. 112, 7954-7959 (2015)]. This predicts the involvement of spatially defined protein dynamical effects that further tune the donor/acceptor distance and geometry as well as the electrostatics of the reactants. Here, we present a hydrogen/deuterium exchange (HDX)-mass spectrometric study of wild type and mutant COMT, comparing temperature dependences of HDX against corresponding kinetic and cofactor binding parameters. The data show that the impaired Tyr68Ala mutant displays similar breaks in Arrhenius plots of both kinetic and HDX properties that are absent in the wild type enzyme. The spatial resolution of HDX below a break point of 15-20 °C indicates changes in flexibility across ∼40% of the protein structure that is confined primarily to the periphery of the AdoMet binding site. Above 20 °C, Tyr68Ala behaves more like WT in HDX, but its rate and enthalpic barrier remain significantly altered. The impairment of catalysis by Tyr68Ala can be understood in the context of a mutationally induced alteration in protein motions that becomes manifest along and perpendicular to the primary group transfer coordinate.


Assuntos
Catecol O-Metiltransferase/química , Motivos de Aminoácidos , Domínio Catalítico , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Humanos , Espectrometria de Massa com Troca Hidrogênio-Deutério , Simulação de Dinâmica Molecular , Mutação
6.
Sci Rep ; 10(1): 7497, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367059

RESUMO

Sleep bruxism (SB) and obstructive sleep apnea (OSA) are co-occurring sleep conditions. The study aimed to evaluate the association of selected single-nucleotide polymorphisms (SNPs) occurring within the genes of the serotonin and dopamine pathways in SB and OSA and investigate the relationship between them. The study group included 100 Caucasian patients. SB and OSA were diagnosed in 74 and 28 patients, respectively. In addition, 125 unrelated Caucasian healthy blood donors served as randomly selected controls to enable comparison of polymorphisms. The following SNPs were analyzed: rs2770304 and rs6313 within the serotonin receptor encoding gene (HTR2A), rs4680 polymorphism of the catechol-O-methyltransferase (COMT) gene, and rs686 within the dopamine receptor (DRD1) encoding gene. The prevalence of the DRD1 rs686 G variant (GG homozygosity) was found to be high in the study group compared to the control group. Bruxism episode index (BEI) was found to be significantly increased in the HTR2A rs6313 TT homozygotes compared to the heterozygous patients. Moreover, within a group of the HTR2A rs2770304 TT homozygous cases, a statistically significant correlation was observed between BEI and apnea-hypopnea index. These results indicate that DRD1 rs686 may potentially affect predisposition to SB, that HTR2A rs6313 SNP may be involved in SB pathogenesis, and that HTR2A rs2770304 polymorphism might contribute to the association between SB and OSA. This suggests a possible genetic contribution to the etiology of primary SB.


Assuntos
Catecol O-Metiltransferase/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina/genética , Receptores de Dopamina D1/genética , Síndromes da Apneia do Sono/genética , Bruxismo do Sono/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Arch Med Res ; 51(1): 13-20, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32086104

RESUMO

BACKGROUND: Several studies indicated that antipsychotic treatment response and side effect manifestation can be different due to inter-individual variability in genetic variations. AIM OF THE STUDY: Here we perform a case-control study to explore a potential association between schizophrenia and variants within the antipsychotic drug molecular targets (DRD1, DRD2, DRD3, HTR2A, HTR6) and metabolizing enzymes (CYP2D6, COMT) genes in Armenian population including also analysis of their possible relationship with disease clinical symptoms. METHODS: A total of 18 SNPs was studied in patients with schizophrenia (n = 78) and healthy control subjects (n = 77) using MassARRAY genotyping. RESULTS: We found that two studied genetic variants, namely DRD2 rs4436578*C and HTR2A rs6314*A are underrepresented in the group of patients compared to healthy subjects. After the correction for multiple testing, the rs4436578*C variant remained significant while the rs6314*A reported borderline significance. No significant differences in minor allele frequencies for other studied variants were identified. Also, a relationship between the genotypes and age of onset as well as disease duration has been detected. CONCLUSIONS: The DRD2 rs4436578*C genetic variant might have protective role against schizophrenia, at least in Armenians.


Assuntos
Catecol O-Metiltransferase/genética , Citocromo P-450 CYP2D6/genética , Polimorfismo de Nucleotídeo Único , Receptores Dopaminérgicos/genética , Receptores de Serotonina/genética , Esquizofrenia/genética , Adulto , Idoso , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Dopamina/genética , Dopamina/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Serotonina/genética , Serotonina/metabolismo , Adulto Jovem
8.
Sci Rep ; 10(1): 2134, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034175

RESUMO

Previous studies have shown that face-specific recognition ability (FRA) is heritable; however, the neural basis of this heritability is unclear. Candidate gene studies have suggested that the catechol-O-methyltransferase (COMT) rs4680 polymorphism is related to face perception. Here, using a partial least squares (PLS) method, we examined the multivariate association between 12 genotypes of 4 COMT polymorphisms (rs6269-rs4633-rs4818-rs4680) and multimodal MRI phenotypes in the human fusiform face area (FFA), which selectively responds to face stimuli, in 338 Han Chinese adults (mean age 20.45 years; 135 males). The MRI phenotypes included gray matter volume (GMV), resting-state fractional amplitude of low-frequency fluctuations (fALFF), and face-selective blood-oxygen-level-dependent (BOLD) responses (FS). We found that the first COMT-variant component (PLS1) was positively associated with the FS but negatively associated with the fALFF in the FFA. Moreover, participants with the COMT heterozygous-HEA-haplotype showed higher PLS1 FFA-MRI scores, which were positively associated with the FRA in an old/new face recognition task, than those with the COMT homozygous HEA haplotype and HEA non-carriers, suggesting that individuals with an appropriate (intermediate) level of dopamine activity in the FFA might have better FRA. In summary, our study provides empirical evidence for the genetic and neural basis for the heritability of face recognition and informs the formation of neural module functional specificity.


Assuntos
Catecol O-Metiltransferase/genética , Face/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Reconhecimento Psicológico/fisiologia , Lobo Temporal/fisiologia , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Fenótipo , Adulto Jovem
9.
Exp Brain Res ; 238(2): 477-486, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31960101

RESUMO

Having reported associations between catechol-O-methyltransferase (COMT) genotypes at SNPs rs4818 and rs4680 with levels of soluble COMT (S-COMT) in human dorsolateral prefrontal cortex (DLPFC), we postulated that changes in the levels of cortical S-COMT could impact on behavioural abilities associated with COMT genotype through S-COMT-mediated changes in gene expression. To test this hypothesis, we have examined the relationships between COMT genotypes and gene expression measured using the Affymetrix™ Human Exon 1.0 ST Array in the DLPFC from 141 individuals, some of whom had had a psychiatric disorder. There were significant differences in levels of expression of 15 genes between individuals with a homozygous genotype at rs4818 (GG vs CC), compared to differences in levels of expression of 6 genes between homozygotes at rs4680 (GG vs AA); levels of expression of CEP128, EFCAB13, and FAM133A differed between homozygotes at both SNPs. Fourteen of the genes differentially expressed in the DLPFC according to COMT genotypes have oestrogen receptor elements and their expression could, therefore, be regulated by catecholestrogens, which are substrates for COMT that occupy and activate oestrogen receptors. In addition, the changes in gene expression between the homozygotes at rs4818 or rs4680 would be expected to impact on neuronal function, synaptic plasticity, cognition, and attention. These data would support a hypothesis that the mechanism underlying the association between COMT genotype and cognition involves differential changes in cortical gene expression.


Assuntos
Catecol O-Metiltransferase/genética , Cognição/fisiologia , Córtex Pré-Frontal/metabolismo , Adulto , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/fisiopatologia
10.
Br J Anaesth ; 124(3): e117-e130, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31955857

RESUMO

A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population.


Assuntos
Cesárea/efeitos adversos , Dor Crônica/etiologia , Parto Obstétrico/efeitos adversos , Analgésicos Opioides/uso terapêutico , Catecol O-Metiltransferase/genética , Dor Crônica/prevenção & controle , Cicatriz/complicações , Feminino , Humanos , Períneo , Gravidez , Receptores Opioides mu/genética , Fatores de Risco
11.
Gene ; 734: 144333, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31972309

RESUMO

Multiple antidepressive treatment methods are widely used in the clinic, but different patients showed considerable differences in response to the same treatment. The catechol-O-methyltransferase (COMT) rs4680 polymorphism is involved in the antidepressive treatment reaction; however, the results in different studies are inconsistent. Thus, we performed a meta-analysis to explore the association of the COMT rs4680 polymorphism with the treatment response in major depressive disorder (MDD) patients. An online search was performed through PubMed, EMBASE and the Cochrane library up to December 2018. The odds ratios (ORs), 95% confidence intervals (95% CI) and heterogeneity were calculated in four genetic models. Subgroup analysis and Galbraith plot were carried out to detect the potential source of heterogeneity. Sensitivity and publication bias analyses were performed to identify the reliability of the results. A total of 11 studies involving 2845 individuals were included in this meta-analysis. The results of the subgroup analysis indicated that patients who carried the G allele had remission or a better response to electroconvulsive therapy (ECT) in four genetic models. Excluding the studies that might lead to heterogeneity, overall ORs were recalculated, and no obvious association between rs4680 polymorphism and therapeutic reaction was detected in the allelic, recessive and additive models. In the dominant model, COMT rs4680 variants showed significant associations with antidepressive treatment, but the result was highly dependent on the individual study. In addition, the patients with the GG or AG + GG genotype in comparison to AA were associated with a better response to ECT treatment. However, due to the small number of studies using ECT treatment, we suggest that more research should be performed to verify this result.


Assuntos
Antidepressivos/uso terapêutico , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Polimorfismo Genético , Biomarcadores Farmacológicos , Estudos de Associação Genética , Humanos , Metionina , Resultado do Tratamento , Valina
12.
Depress Anxiety ; 37(3): 261-272, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944487

RESUMO

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression. METHOD: The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects. RESULTS: The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively. CONCLUSIONS: These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Estimulação Transcraniana por Corrente Contínua , Transtorno Bipolar/terapia , Catecol O-Metiltransferase/genética , Método Duplo-Cego , Humanos , Córtex Pré-Frontal , Resultado do Tratamento
13.
Braz J Psychiatry ; 42(2): 128-135, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31721892

RESUMO

OBJECTIVE: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. METHODS: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. RESULTS: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. CONCLUSION: Larger, combined datasets are necessary to identify candidate genes for tDCS response.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Resultado do Tratamento , Triptofano Hidroxilase/genética , Adulto Jovem
14.
Psychiatr Genet ; 30(1): 10-18, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31568068

RESUMO

INTRODUCTION: As schizophrenia is a complex mental disorder and the outcome of gene-gene-environmental interactions, there are different possible pathophysiological mechanisms in different schizophrenia subtypes corresponding to various risk factors. This study was aimed at examining the impact of one of the most likely interactions, that is, 'dopamine and stress', in schizophrenia pathogenesis. METHODS: Here, we investigated the interaction between 'war-related psychological trauma' without brain trauma and catechol-O-methyltransferase gene. Using real-time PCR analysis we measured catechol-O-methyltransferase gene expression level in the blood cells of 66 male subjects in four groups, namely veteran schizophrenia patients as 'stress-exposed schizophrenia' (S-schizophrenia), their healthy brothers as 'their genetically closest relatives' (S-siblings), schizophrenia patients without any history of significant stress as 'non-stress-exposed schizophrenia' (NoS-schizophrenia), and the control group. The results were analyzed by Relative Expression Software Tool 2009 software. RESULTS: The catechol-O-methyltransferase gene expression was not significantly different between the S-schizophrenia and NoS-schizophrenia groups. However, compared to the control group, the catechol-O-methyltransferase expression was significantly decreased in three groups of S-schizophrenia, their healthy siblings, and NoS-schizophrenia patients. CONCLUSION: This data supports that reduced blood catechol-O-methyltransferase expression, which may be associated with higher dopamine level, is involved both in stress-induced and non-stress-induced schizophrenia.


Assuntos
Catecol O-Metiltransferase/genética , Esquizofrenia/genética , Estresse Psicológico/genética , Adulto , Catecol O-Metiltransferase/sangue , Catecol O-Metiltransferase/metabolismo , Dopamina/sangue , Dopamina/metabolismo , Dopamina/fisiologia , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/metabolismo , Irmãos , Estresse Psicológico/metabolismo
15.
Pharmacogenet Genomics ; 30(1): 5-8, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651722

RESUMO

Fentanyl has been implicated as a major contributor to the increased number of opioid overdose deaths. Surprisingly, little is known about the pharmacogenetic influences on fentanyl pharmacokinetics or pharmacodynamics. Pharmacogenetic studies of fentanyl are based largely on small sample sizes and have examined the potential association of only a small number of high frequency variants in selected candidate genes primarily with postoperative pain. Few data are available on low frequency variants, variants from racially/ethnically diverse populations, or on other phenotypes. Given the genetic diversity of low frequency variants, DNA sequencing may be needed to determine whether pharmacogenetic differences may contribute to lethal opioid overdoses.


Assuntos
Overdose de Drogas/genética , Fentanila/efeitos adversos , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Catecol O-Metiltransferase/genética , Estudos de Associação Genética , Humanos , Variantes Farmacogenômicos , Receptores Opioides mu/genética
16.
Dev Psychobiol ; 62(2): 181-190, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31372986

RESUMO

The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d') and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.


Assuntos
Catecol O-Metiltransferase/genética , Desenvolvimento Infantil/fisiologia , Função Executiva/fisiologia , Inibição Psicológica , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Desempenho Psicomotor/fisiologia
17.
Eur Arch Psychiatry Clin Neurosci ; 270(2): 229-235, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31289926

RESUMO

A recent study reported a negative association between a putatively functional dopamine (DA) polygenic score, indexing higher levels of DA signaling, and depressive symptoms. We attempted to replicate this association using data from the Duke Neurogenetics Study. Our replication attempt was made in a subsample of 520 non-Hispanic Caucasian volunteers (277 women, mean age 19.78 ± 1.24 years). The DA polygenic score was based on the following five loci: rs27072 (SLC6A3/DAT1), rs4532 (DRD1), rs1800497 (DRD2/ANKK1), rs6280 (DRD3), and rs4680 (COMT). Because the discovery sample in the original study consisted mostly of Asian participants, we also conducted a post hoc analysis in a smaller subsample of Asian volunteers (N = 316, 179 women, mean age 19.61 ± 1.32 years). In the primary sample of non-Hispanic Caucasians, a linear regression analysis controlling for sex, age, socioeconomic status (SES), body mass index, genetic ancestry, and both early and recent life stress, revealed that higher DA polygenic scores were associated with higher self-reported symptoms of depression. This was in contrast to the original association of higher DA polygenic scores and lower depressive symptoms. However, the direction of the association in our Asian subsample was consistent with this original finding. Our results also suggested that compared to the Asian subsample, the non-Hispanic Caucasian subsample was characterized by higher SES, lower early and recent life stress, and lower depressive symptoms. These differences may have contributed to the observed divergence in associations. Collectively, the current findings add to evidence that specific genetic associations may differ between populations and further encourage explicit modeling of race/ethnicity in examining the polygenic nature of depressive symptoms and depression.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Depressão/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Grupo com Ancestrais do Continente Europeu/genética , Receptores Dopaminérgicos/genética , Adolescente , Adulto , Catecol O-Metiltransferase/genética , Feminino , Humanos , Masculino , Herança Multifatorial , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Adulto Jovem
18.
Dev Sci ; 23(2): e12889, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31336006

RESUMO

Dopamine transmission in the prefrontal cortex (PFC) supports working memory (WM), the temporary holding, processing and manipulation of information in one's mind. The gene coding the catechol-O-methyltransferase (COMT) enzyme, which degrades dopamine, in particular in the PFC, has a common single nucleotide polymorphism leading to two versions of the COMT enzyme which vary in their enzymatic activity. The methionine (Met) allele has been associated with higher WM performance and lower activation of the PFC in executive function tasks than the valine (Val) allele. In a previous study, COMT genotype was associated with performance on verbal and visuospatial WM tasks in adults, as well as with performance on a novel social WM paradigm that requires participants to maintain and manipulate information about the traits of their friends or family over a delay. Here, data collected in children and adolescents (N = 202) were compared to data from the adult sample (N = 131) to investigate possible age differences in genetic associations. Our results replicate and extend previous work showing that the pattern of superior WM performance observed in Met/Met adults emerges during development. These findings are consistent with a decrease in prefrontal dopamine levels during adolescence. Developmentally moderated genetic effects were observed for both visuospatial and social WM, even when controlling for non-social WM performance, suggesting that the maintenance and manipulation of social information may also recruit the dopamine neurotransmitter system. These findings show that development should be considered when trying to understand the impact of genetic polymorphisms on cognitive function.


Assuntos
Catecol O-Metiltransferase/genética , Dopamina/genética , Memória de Curto Prazo/fisiologia , Adolescente , Adulto , Criança , Cognição/fisiologia , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal
19.
Eur J Pain ; 24(2): 398-412, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31661578

RESUMO

BACKGROUND: This study examined the extent to which genetic variability modifies Transcutaneous Electrical Nerve Stimulation (TENS) effectiveness in osteoarthritic knee pain. METHODS: Seventy-five participants with knee osteoarthritis were randomly assigned to either: (a) High-frequency TENS, (b) Low-frequency TENS or (c) Transient Placebo TENS. Pain measures were collected pre- and post-treatment. Participants were genotyped on genes implicated in central or peripheral pain pathways: NGFB, NTRK1, EDNRA, EDNRB, EDN1, OPRM1, TAC1, TACR1, BDNF, BDKRB1, 5HTT, COMT, ESR2, IL6 and IL1B. Genetic association using linear regression modelling was performed separately for the transient placebo TENS subjects, and within the High-frequency TENS + Low-frequency TENS participants, including TENS level as a covariate. RESULTS: In the placebo group, SNPs rs165599 (COMT) was significantly associated with an increased heat pain threshold (ß = -1.87; p = .003) and rs6827096 (EDNRA) with an increased resting pain (ß = 2.68; p = .001). Within the treatment groups, TENS effectiveness was reduced by the SNP rs6537485 (EDNRA) minor allele in relationship to mechanical sensation (ß = 184.13; p = 5.5E-9). Individuals with the COMT rs4680 minor allele reported lowered pain at rest after TENS (ß = -42.30; p = .001), with a higher magnitude of pain reduction (28 unit difference) in the low-frequency TENS group compared to the high-frequency TENS group (ß = 28.37; p = .0004). CONCLUSIONS: EDNRA and COMT are implicated in osteoarthritic knee pain and provide a basis for tailoring TENS interventions according to individual characteristics. SIGNIFICANCE: Findings from this study demonstrate that genetic variation within the COMT and EDNRA genes influences the effectiveness of TENS, a non-pharmacologic pain-reduction intervention, in the context of osteoarthritic knee pain. Evidence such as this may contribute to risk models that provide a clinically useful tool for personalizing TENS interventions according to individual characteristics in order to best control pain and maximize functional status.


Assuntos
Osteoartrite do Joelho , Estimulação Elétrica Nervosa Transcutânea , Catecol O-Metiltransferase/genética , Genótipo , Humanos , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/terapia , Dor/genética , Manejo da Dor , Receptor de Endotelina A/genética , Receptores Opioides mu
20.
Int J Med Sci ; 16(11): 1461-1465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673237

RESUMO

Catechol-O-Methyltranferase (COMT) plays a crucial role in the removal of cortical dopamine and is strongly implicated in human executive function. Numerous studies have reported associations of the COMT Val158Met (rs4680) polymorphism with executive function in healthy subjects. However, little work has investigated this in the Thai population and the relationship of age and education with this association remains unclear. Therefore, this study was designed to investigate the association of this polymorphism of the COMT gene with executive cognitive brain function in healthy subjects and the relationship with age and education. The Wisconsin Card Sorting Test (WCST) was performed to assess executive function in 254 healthy Thai subjects (aged 20-72 years). The results showed a significant association of rs4680 with executive function, in which Val/Met heterozygotes demonstrated better cognitive set shifting performance. Moreover, Met allele carriers showed a significantly stronger effect in the categories completed score than did Val homozygotes. Furthermore, age and education also showed a significant association with COMT genotype and WCST. These results revealed that executive cognitive function is associated with COMT genotype and influenced by age and/or education level in a Thai sample.


Assuntos
Catecol O-Metiltransferase/genética , Cognição , Função Executiva , Predisposição Genética para Doença , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Catecóis/metabolismo , Dopamina/metabolismo , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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