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1.
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
2.
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
3.
Psychiatr Danub ; 31(2): 241-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291232

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disorder that occurs in some people who have experienced a severe traumatic event. Several genetic studies suggest that gene encoding proteins of catechol-O-methyl-transferase (COMT) may be relevant for the pathogenesis of PTSD. Some researchers suggested that the elevation of interleukin-6 (IL6) correlates with major depression and PTSD. The aim of this study was to investigate whether the single nucleotide polymorphisms COMT rs4680 (Val158Met) and IL6 rs1800795 are associated with PTSD and contribute to the severity of PTSD symptoms. SUBJECTS AND METHODS: This study comprised 747 participants that experienced war between 1991 and 1999 in the South Eastern Europe conflicts. COMT rs4680 (Val158Met) and IL6 rs1800795 genotypes were determined in 719 participants (369 with and 350 without PTSD). The Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) questionnaire and the Brief Symptom Inventory (BSI) were used for data collection. RESULTS: Regarding the COMT gene polymorphism, the results of the regression analyses for BSI total score were significant in the lifetime PTSD group in the dominant (P=0.031) and the additive allelic model (P=0.047). Regarding the IL6 gene, a significant difference was found for the recessive model predicting CAPS total score in the lifetime PTSD group (P=0.048), and indicated an association between the C allele and higher CAPS scores. n the allelic, genotypic and rezessive model, the results for BSI total score were significant in the lifetime PTSD group (P=0.033, P=0.028 and P=0.009), suggesting a correlation of the C allele with higher BSI scores. CONCLUSION: Although our nominally significant results did not withstand correction for multiple tests they may support a relevance of the COMT (Val158Met) and IL6 rs1800795 polymorphism for aspects of PTSD in war traumatized individuals.


Assuntos
Catecol O-Metiltransferase/genética , Interleucina-6/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Conflitos Armados/psicologia , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Brain Struct Funct ; 224(8): 2619-2630, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31332515

RESUMO

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.


Assuntos
Encéfalo/metabolismo , Catecol O-Metiltransferase/genética , Receptores Dopaminérgicos/genética , Adolescente , Adulto , Mapeamento Encefálico , Feminino , Expressão Gênica , Haplótipos , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores Dopaminérgicos/metabolismo , Adulto Jovem
5.
Psychopharmacology (Berl) ; 236(11): 3209-3219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31187152

RESUMO

RATIONALE: The catechol-O-methyl transferase (COMT) enzyme has been implicated in determining dopaminergic tone and the effects of delta-9-tetrahydrocannabinol (THC) in the human brain. OBJECTIVE: This study was designed to evaluate the effect of (1) a functional polymorphism and (2) acute pharmacological inhibition of COMT on the acute response to THC in humans. METHODS: Sub-study I: The effect of intravenous (IV) THC (0.05 mg/kg) was investigated in 74 healthy subjects genotyped for the COMT rs4680 (Val/Met) polymorphism in a 2-test-day double-blind, randomized, placebo-controlled study. Sub-study II: COMT rs4680 homozygous subjects (Val/Val and Met/Met) from sub-study I received the COMT enzyme inhibitor tolcapone (200 mg) followed by IV THC or placebo on two additional test days. Subjective, behavioral, and cognitive data were obtained periodically on each test day. RESULTS: Sub-study I: Val/Val individuals were most sensitive to THC-induced attention and working memory deficits. In contrast, the psychotomimetic and subjective effects of THC were not influenced by COMT genotype. Sub-study II: Tolcapone reduced THC-induced working memory deficits, but not THC's psychotomimetic effects. Tolcapone and COMT genotype (met/met) were associated with an increased report of feeling "mellow." CONCLUSIONS: The interaction between COMT rs4680 polymorphisms and tolcapone on the cognitive, but not on the psychotomimetic and overall subjective effects of THC, suggests that modulation of dopaminergic signaling may selectively influence specific cannabinoid effects in healthy individuals. The role of dopaminergic signaling in the cognitive effects of cannabinoids should be considered in drug development efforts targeting these effects. CLINICALTRIALS.GOV REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00678730?term=NCT00678730&rank=1 ClinicalTrials.gov Identifier: NCT00678730.


Assuntos
Encéfalo/metabolismo , Inibidores de Catecol O-Metiltransferase/administração & dosagem , Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Dronabinol/administração & dosagem , Variação Genética/genética , Administração Intravenosa , Adolescente , Adulto , Atenção/efeitos dos fármacos , Atenção/fisiologia , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Polimorfismo Genético/genética , Adulto Jovem
6.
Appl Microbiol Biotechnol ; 103(12): 4881-4887, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053915

RESUMO

How cells of the fission yeast Schizosaccharomyces pombe respond to alkaline stress is not well understood. Here, to elucidate the molecular mechanism underlying the alkaline stress response in S. pombe, we performed DNA microarray analysis. We found that a homolog of human catechol O-methyltransferase 2 (COMT2) is highly upregulated in S. pombe cells exposed to alkaline conditions. We designated the S. pombe homolog as cmt2+ and also identified its paralog, cmt1+, in the S. pombe genome. Reverse transcription PCR confirmed that both cmt1+ and cmt2+ are upregulated within 1 h of exposure to alkaline stress and downregulated within 30 min of returning to an acidic environment. Moreover, we verified that recombinant Cmt proteins exhibit catechol O-methyltransferase activity. To further characterize the expression of cmt1+ and cmt2+, we carried out an EGFP reporter assay using their promoter sequences, which showed that both genes respond not only to alkaline but also to salt stress. Collectively, our findings indicate that the cmt promoter might be an advantageous expression system for use in S. pombe under alkaline culture conditions.


Assuntos
Antiácidos/farmacologia , Catecol O-Metiltransferase/genética , Estresse Salino , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/enzimologia , Catecol O-Metiltransferase/metabolismo , Clonagem Molecular , Regulação Fúngica da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Homologia de Sequência de Aminoácidos , Regulação para Cima
7.
Genes (Basel) ; 10(5)2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137904

RESUMO

Xenobiotic-metabolizing enzymes (XME) mediate the body's response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition. We hypothesized that the variability of these genes influencing the interaction with the exposome could affect the individual chance of becoming long-lived. We tested this hypothesis by screening a cohort of 1112 individuals aged 20-108 years for 35 variants in 23 XME genes. Four variants in different genes (CYP2B6/rs3745274-G/T, CYP3A5/rs776746-G/A, COMT/rs4680-G/A and ABCC2/rs2273697-G/A) differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65-89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene-environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits.


Assuntos
Envelhecimento/genética , Inativação Metabólica/genética , Longevidade/genética , Xenobióticos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Catecol O-Metiltransferase/genética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Itália/epidemiologia , Masculino , Metabolômica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
8.
Neuropsychobiology ; 78(2): 79-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096213

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder accounting for 60-70% of dementia cases. Genetic origin accounts for 49-79% of disease risk. This paper aims to investigate the association of 17 polymorphisms within 7 genes involved in neurotransmission (COMT, HTR2A, PPP3CC, RORA, SIGMAR1, SIRT1, and SORBS3) and AD. METHODS: A Greek and an Italian sample were investigated, for a total of 156 AD subjects and 301 healthy controls. Exploratory analyses on psychosis and depression comorbidities were performed, as well as on other available clinical and serological parameters. RESULTS: AD was associated with rs4680 within the COMT gene in the total sample. Trends of association were found in the 2 subsamples. Some nominal associations were found for the depressive phenotype. rs10997871 and rs10997875 within SIRT1 were nominally associated with depression in the total sample and in the Greek subsample. rs174696 within COMT was associated with depression comorbidity in the Italian subsample. DISCUSSION: Our data support the role of COMT, and particularly of rs4680, in the pathogenesis of AD. Furthermore, the SIRT1 gene seems to modulate depressive symptomatology in the AD population.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Catecol O-Metiltransferase/genética , Inflamação/epidemiologia , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Sirtuína 1/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Comorbidade , Feminino , Predisposição Genética para Doença/genética , Grécia/epidemiologia , Humanos , Inflamação/genética , Itália/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Transmissão Sináptica/genética
9.
Dev Psychopathol ; 31(3): 1111-1126, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31057130

RESUMO

This study tested whether the association between interparental conflict and adolescent externalizing symptoms was moderated by a polygenic composite indexing low dopamine activity (i.e., 7-repeat allele of DRD4; Val alleles of COMT; 10-repeat variants of DAT1) in a sample of seventh-grade adolescents (Mean age = 13.0 years) and their parents. Using a longitudinal, autoregressive design, observational assessments of interparental conflict at Wave 1 predicted increases in a multi-informant measurement of youth externalizing symptoms 2 years later at Wave 3 only for children who were high on the hypodopaminergic composite. Moderation was expressed in a "for better" or "for worse" form hypothesized by differential susceptibility theory. Thus, children high on the dopaminergic composite experienced more externalizing problems than their peers when faced with more destructive conflicts but also fewer externalizing problems when exposed to more constructive interparental conflicts. Mediated moderation findings indicated that adolescent reports of their emotional insecurity in the interparental relationship partially explained the greater genetic susceptibility experienced by these children. More specifically, the dopamine composite moderated the association between Wave 1 interparental conflict and emotional insecurity 1 year later at Wave 2 in the same "for better" or "for worse" pattern as externalizing symptoms. Adolescent insecurity at Wave 2, in turn, predicted their greater externalizing symptoms 1 year later at Wave 3. Post hoc analyses further revealed that the 7-repeat allele of the dopamine receptor D4 (DRD4) gene was the primary source of plasticity in the polygenic composite. Results are discussed as to how they advance process-oriented Gene x Environment models of emotion regulation.


Assuntos
Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Emoções/fisiologia , Conflito Familiar/psicologia , Comportamento Problema/psicologia , Receptores de Dopamina D4/genética , Adolescente , Agressão/psicologia , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Pais/psicologia
10.
Int J Mol Sci ; 20(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991630

RESUMO

Studies indicate the heritable nature of affective temperament, which shows personality traits predisposing to the development of mental disorders. Dopaminergic gene polymorphisms such as DRD4, COMTVal158Met, and DAT1 have been linked to affective disorders in obesity. Due to possible correlation between the aforementioned polymorphisms and the affective temperament, the aim of our research was to investigate this connection in an obese population. The study enrolled 245 obese patients (178 females; 67 males). The affective temperament was assessed using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire (TEMPS-A). Genetic polymorphisms of DAT1, COMTVal158Met and DRD4 were collected from peripheral blood sample and determined using a polymerase chain reaction (PCR). Only in COMT polymorphisms, the cyclothymic and irritable dimensions were significantly associated with Met/Val carriers (p = 0.04; p = 0.01). Another interesting finding was the correlation between the affective temperament and age in men and women. We assume that dopamine transmission in heterozygotes of COMT may determine the role of the affective temperament in obese persons. Dopaminergic transmission modulated by COMT may be responsible for a greater temperament expression in obese individuals. To our knowledge, this is the first study describing the role of affective temperament in the obese population, but more research is needed in this regard.


Assuntos
Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Transtornos do Humor/genética , Obesidade/genética , Polimorfismo Genético , Receptores de Dopamina D4/genética , Adulto , Dopamina/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Obesidade/complicações , Temperamento
11.
Food Chem Toxicol ; 128: 35-45, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935952

RESUMO

Catechol-containing polyphenols present in coffee and tea, while serving as excellent substrates for catechol-O-methyltransferase (COMT)-catalyzed O-methylation, can also operate as COMT inhibitors. However, little is known about the relationship between COMT and the characteristic phenolics present in extra virgin olive oil (EVOO). We here selected the EVOO dihydroxy-phenol oleacein for a computational study of COMT-driven methylation using classic molecular docking/molecular dynamics simulations and hybrid quantum mechanical/molecular mechanics, which were supported by in vitro activity studies using human COMT. Oleacein could be superimposed onto the catechol-binding site of COMT, maintaining the interactions with the atomic positions involved in methyl transfer from the S-adenosyl-L-methionine cofactor. The transition state structure for the meta-methylation in the O5 position of the oleacein benzenediol moiety was predicted to occur preferentially. Enzyme analysis of the conversion ratio of catechol to O-alkylated guaiacol confirmed the inhibitory effect of oleacein on human COMT, which remained unaltered when tested against the protein version encoded by the functional Val158Met polymorphism of the COMT gene. Our study provides a theoretical determination of how EVOO dihydroxy-phenols can be metabolized via COMT. The ability of oleacein to inhibit COMT adds a new dimension to the physiological and therapeutic utility of EVOO secoiridoids.


Assuntos
Aldeídos/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Azeite de Oliva/química , Fenóis/farmacologia , Aldeídos/isolamento & purificação , Catecol O-Metiltransferase/genética , Catecóis/metabolismo , Humanos , Metionina/genética , Metilação , Simulação de Acoplamento Molecular , Fenóis/isolamento & purificação , Polimorfismo Genético , Especificidade por Substrato , Valina/genética
12.
Arch Dermatol Res ; 311(4): 309-315, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30840133

RESUMO

Psoriasis is a multigene and multifactorial skin disease with heterogeneous genetic inheritance. Mental disorders participate in the development of psoriasis as predisposing factors; a correlation of dermatological diseases with pathological anxiety and stress was shown. Meanwhile, there are no studies describing molecular mechanisms of the linkages between psycho-emotional disorders and skin diseases. The aim of this study is to find the associations between SNP in genes COMT (rs4680), DBH (rs141116007), CCKAR (rs1800857) and CCKBR (rs1805002), and psoriasis. Patients were selected according to the 10th revision of International Classification of Diseases (L-40). The sample size was 88 patients. The size of the control sample (population control) was 365 people. Genotyping was performed using PCR-RFLP and real-time PCR. Statistical analysis was performed using WinPepi software. Identification of complex genotypes was performed by the Monte Carlo method using APSampler 3.6.1 algorithm. Among the studied genes, only GA genotype of COMT gene is significantly associated with psoriasis [χ2 = 19.163 (p = 1.3E-5), F (p) = 1.2E-5, OR 3.47 (CI 99% = 1.61-7.91)]. At the moment, the functional significance of this phenomenon is difficult to explain.


Assuntos
Transtornos de Ansiedade/epidemiologia , Catecol O-Metiltransferase/genética , Dopamina beta-Hidroxilase/imunologia , Genótipo , Psoríase/genética , Receptor de Colecistocinina A/genética , Receptor de Colecistocinina B/genética , Algoritmos , Biologia Computacional , Dopamina beta-Hidroxilase/genética , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Psoríase/epidemiologia , Federação Russa
13.
Acta Oncol ; 58(5): 537-547, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822178

RESUMO

Background: Cancer-related cognitive impairment (CRCI) is a commonly reported complaint among non-CNS cancer patients. Even subtle CRCI may have detrimental effects on quality of life and identifying patients at increased risk for CRCI to improve survivorship care is important. In the present paper, we systematically reviewed available studies of possible genetic risk factors for developing CRCI. Methods: Keyword-based systematic searches were undertaken on 24 July 2018 in PubMed, Web of Science, The Cochrane Library, and CINAHL. Three authors independently evaluated full-texts of identified papers and excluded studies with registration of reasons. Seventeen studies reporting results from 14 independent samples were included for review. Two authors independently quality assessed the included studies. The review was preregistered with PROSPERO (CRD42018107689). Results: Ten studies investigated apolipoprotein E (APOE), with four studies reporting that carrying at least one risk allele (APOE4 (ε4)) was associated with CRCI, while six studies found no association. The remaining identified genetic risk variants associated with CRCI located in: COMT, four DNA repair genes, five oxidative stress genes, 22 genes related to breast cancer phenotype, and GNB3. No associations were found between CRCI and genes coding for interleukin-6 (IL6), tumor necrosis factor alpha (TNF), interleukin 1 beta (IL1B), and brain-derived neurotropic factor (BDNF). With the exception of APOE, the genetic risk factors had only been investigated in one or two studies each. Conclusions: Overall, the available evidence of possible genetic risk factors for CRCI is limited. While some research suggests a role for the ε4 allele, the literature is generally inconsistent, and the currently available evidence does not allow clear-cut conclusions regarding the role of genetic factors in the development of CRCI. Larger genetic studies and studies investigating additional genetic variants are needed to uncover genetic risk factors for CRCI.


Assuntos
Transtornos Cognitivos/genética , Neoplasias/complicações , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Transtornos Cognitivos/etiologia , Dano ao DNA/genética , Predisposição Genética para Doença , Humanos , Inflamação/genética , Neoplasias/genética , Neoplasias/terapia , Estresse Oxidativo/genética
14.
J Youth Adolesc ; 48(4): 655-667, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30830534

RESUMO

To date, several gene-by-environment (G×E) meta-analyses have been conducted to provide cumulative G×E evidence from previous inconsistent empirical studies; however, these meta-analyses have mainly focused on the serotonin transporter gene (5-HTTLPR). The present study aimed to conduct the first meta-analysis that tested whether and how an important dopaminergic gene-the catechol-O-methyltransferase (COMT) gene contributed to differences in child and adolescent environmental sensitivity. A total of 22 studies with 20,528 participants involving in various developmental outcomes (e.g., externalizing problems, emotional problems, cognitive development and social behaviors) met the inclusion criteria. The pooled effect size of environment-outcome associations in the Met-allele carriers (r = 0.11, 95% CI = [0.07, 0.15], p < .001) did not significantly differ from that in the Val/Val homozygotes (r = 0.14, 95% CI = [0.08, 0.20], p < 0.001) (Qcontrast (1) = 0.37, p = 0.54). The aggregated Liptak-Stouffer Z-score that combined the p-values of the COMT-environment interaction yield a nonsignificant result (p = 0.52). Moreover, outcome domain, sample age, ethnicity and assessment methods for the environment and the outcome did not moderate the effect sizes. Thus far, the COMT Val158Met polymorphism fails to explain the differences in sensitivity to environment. Future studies might incorporate more factors, such as polygenic effects of genetic pathways, epigenetics (EpiG) processing and sexual dimorphism, into the COMT-environment interaction equation.


Assuntos
Catecol O-Metiltransferase/genética , Interação Gene-Ambiente , Adolescente , Alelos , Criança , Comportamento Infantil , Desenvolvimento Infantil , Cognição , Feminino , Genótipo , Humanos , Masculino , Polimorfismo Genético
15.
Brain Cogn ; 132: 72-79, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30903983

RESUMO

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.


Assuntos
Catecol O-Metiltransferase/genética , Memória de Curto Prazo/fisiologia , Tempo de Reação/genética , Alelos , Cognição/fisiologia , Potenciais Evocados , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Tempo de Reação/fisiologia , Adulto Jovem
16.
PLoS One ; 14(3): e0214146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897147

RESUMO

Executive dysfunction is common in Parkinson's disease (PD) patients. The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to affect executive functions (EFs) in the prefrontal cortex. The present study attempted to explore the influence of the COMT polymorphism on EFs in patients with PD. Fifty-four PD patients were recruited and underwent neuropsychological assessments for three core EFs. The COMT polymorphism was genotyped using the TaqMan SNP Genotyping Assay. Participants were divided into three study groups: Val homozygotes, heterozygotes, and Met homozygotes. The three COMT genotype groups had significantly different performances in set-shifting [χ2 (2, 54) = 9.717, p = 0.008] and working memory tasks [χ2 (2, 54) = 7.806, p = 0.020]. Post-hoc analyses revealed that PD Val homozygotes performed significantly poorer in the set-shifting task than did either the PD Met homozygotes (z = -2.628, p = 0.009) or PD heterozygotes (z = -2.212, p = 0.027). Our explorative results suggest that the putative level of prefrontal dopamine influenced set-shifting through a "cane-shaped" dopamine level-response relationship. Our results have clinical implications, which may influence PD treatment with dopamine in the future because the optimal dopamine level to maximize EFs may vary based on the clinical course and COMT polymorphism status. Further study recruiting a larger number of participants is needed to confirm our preliminary findings.


Assuntos
Catecol O-Metiltransferase/genética , Função Executiva , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Humanos , Masculino , Memória de Curto Prazo , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia
17.
Percept Mot Skills ; 126(3): 349-365, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30841785

RESUMO

Within the cognitive domain, neuroscience and cognitive psychology researchers have investigated the relationship between handedness and cognitive skills. However, there have been few studies of the three-way association between manual asymmetry, its genetic components, and cognition even though this line of research could further an understanding of asymmetry. One enzyme involved in cognitive functions related to the dopaminergic system and to the prefrontal cortex is the catechol-O-methyltransferase (COMT), and it has a trimodal activity distribution in the human population due to its functional polymorphism known as Val158Met. This study investigated whether this COMT polymorphism is associated with asymmetries in the performance of a manual dexterity task. Forty-two right-handed undergraduate students ( Mage = 25.12, SD = 5.84; 15 women, 27 men) performed two trials each of place and remove conditions of the Grooved Pegboard Test with each hand (right and left), counterbalancing the order of the initial or starting hand. We calculated the mean time to perform the task for both hands on both trials and found, as hypothesized, that the Met/Met group gave a more asymmetrical performance than the Val/Met group under the place condition because dopamine levels reduced flexible behavior for the Val/Met group. We suspect that the place condition requires greater interhemispheric connectivity, as it requires a greater cognitive flexibility, and highly asymmetrical individuals are said to be less flexible. The findings of this study suggest a significant association between the COMT polymorphism and manual asymmetry in healthy populations.


Assuntos
Catecol O-Metiltransferase/genética , Lateralidade Funcional/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Lateralidade Funcional/genética , Humanos , Masculino , Adulto Jovem
18.
Neurosci Bull ; 35(4): 735-742, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30852803

RESUMO

ZNF804A rs1344706 has been identified as one of the risk genes for schizophrenia. However, the neural mechanisms underlying this association are unknown. Given that ZNF804A upregulates the expression of COMT, we hypothesized that ZNF804A may influence brain activity by interacting with COMT. Here, we genotyped ZNF804A rs1344706 and COMT rs4680 in 218 healthy Chinese participants. Amplitudes of low-frequency fluctuations (ALFFs) were applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680. The ALFFs of the bilateral dorsolateral prefrontal cortex showed a significant ZNF804A rs1344706 × COMT rs4680 interaction, manifesting as a U-shaped modulation, presumably by dopamine signaling. Significant main effects were also found. These findings suggest that ZNF804A affects the resting-state functional activation by interacting with COMT, and may improve our understanding of the neurobiological effects of ZNF804A and its association with schizophrenia.


Assuntos
Catecol O-Metiltransferase/genética , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , China , Dopamina/metabolismo , Feminino , Predisposição Genética para Doença/genética , Genótipo , Voluntários Saudáveis , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adulto Jovem
19.
Behav Brain Res ; 364: 225-232, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30738913

RESUMO

Catechol-O-methyltransferase (COMT) gene variants have been reported to be implicated in the pathogenesis of psychotic symptoms in schizophrenia, especially in negative symptoms. These symptoms including apathy, blunted affect, social withdrawal and motor retardation. Neuroimaging studies suggested that negative symptoms appear to be associated with impaired activities of the prefrontal cortex in particular the dorsolateral prefrontal cortex (DLPFC). Given that the COMT gene is highly expressed in the DLPFC, it is poorly understood whether the disease state and COMT val158met polymorphisms have main and interactive effect on the resting state functional connectivity (RSFC) of DLPFC-related pathways. To this end, fifty-five first episode schizophrenia (FES) and fifty-three healthy controls were genotyped using blood samples and underwent magnetic resonance imaging scanning. Seed-based voxel wise functional connectivity analysis was performed by placing bilateral pairs of seeds with DLPFC in area 46 defined by Brodmann's atlas. A two-ways ANCOVA model was performed with val158met genotypes and disease state as the between subjects factors. Significant disease × COMT interactive effect was found mainly in the left DLPFC with the left anterior cingulate cortex, right precuneus, right superior parietal gyrus, which were overlapped with disease main effect. And these RSFC had positive correlations with affective blunting scores in FES patients with val homozygotes, but not with met carriers. Our results showed that the disease and the genotypes in COMT gene have significant interactive effect on RSFC of DLPFC and provided evidence for a disease-dependent pattern of gene action.


Assuntos
Catecol O-Metiltransferase/genética , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Encéfalo/patologia , Mapeamento Encefálico/métodos , Estudos de Casos e Controles , Catecol O-Metiltransferase/metabolismo , Córtex Cerebral/fisiopatologia , China , Feminino , Genótipo , Giro do Cíngulo/fisiopatologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Lobo Parietal/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/metabolismo , Adulto Jovem
20.
Neuroscience ; 404: 396-406, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30742958

RESUMO

Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. Whether the Val158Met polymorphism affects the AMPPI in female adults at different menstrual-cycle phases is unknown. This study examined whether AMPPI and/or PPI are affected by the Val158Met polymorphism in 177 younger-adult females whose menstrual cycles were mutually different across the menstruation, proliferative, or secretory phases. The AMPPI was evaluated by comparing PPI under the condition of the auditory precedence-effect-induced perceptual spatial separation between the prepulse stimulus and a masking noise (PPIPSS) against that under the condition of the precedence-effect-induced perceptual spatial co-location (PPIPSC). The results showed that both the menstrual cycle and the COMT Val158Met polymorphism affected both PPIPSC and PPIPSS, but not the AMPPI (difference between PPIPSS and PPIPSC). Moreover, throughout the menstrual cycle, both PPIPSC and PPIPSS decreased monotonously in Val/Val-carrier participants. However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPIPSC and PPIPSS, but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults.


Assuntos
Atenção/fisiologia , Catecol O-Metiltransferase/genética , Ciclo Menstrual/fisiologia , Metionina/genética , Inibição Pré-Pulso/fisiologia , Valina/genética , Estimulação Acústica , Adolescente , Feminino , Humanos , Ciclo Menstrual/genética , Polimorfismo Genético/genética , Reflexo de Sobressalto , Adulto Jovem
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