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1.
Lancet ; 394(10200): 781-792, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31478502

RESUMO

Alcohol use disorders consist of disorders characterised by compulsive heavy alcohol use and loss of control over alcohol intake. Alcohol use disorders are some of the most prevalent mental disorders globally, especially in high-income and upper-middle-income countries; and are associated with high mortality and burden of disease, mainly due to medical consequences, such as liver cirrhosis or injury. Despite their high prevalence, alcohol use disorders are undertreated partly because of the high stigma associated with them, but also because of insufficient systematic screening in primary health care, although effective and cost-effective psychosocial and pharmacological interventions do exist. Primary health care should be responsible for most treatment, with routine screening for alcohol use, and the provision of a staggered treatment response, from brief advice to pharmacological treatment. Clinical interventions for these disorders should be embedded in a supportive environment, which can be bolstered by the creation of alcohol control policies aimed at reducing the overall level of consumption.


Assuntos
Alcoolismo/epidemiologia , Alcoolismo/terapia , Alcoolismo/diagnóstico , Alcoolismo/genética , Efeitos Psicossociais da Doença , Feminino , Saúde Global , Humanos , Masculino , Programas de Rastreamento , Atenção Primária à Saúde/métodos
2.
Adv Exp Med Biol ; 1193: 221-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368107

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is a member of ALDH family. ALDH1 has been widely recognized for its roles in carcinogenesis and cancer therapy; however, investigation for ALDH2 in cancer is seldom mentioned. The ALDH2 point mutation ALDH2*2 is the most frequent human gene variant, and it is present in approximately 560 million East Asians. ALDH2*2 demonstrates its effect on alcohol consumption limiting and alcoholism developing protection, and this variant is recently found to have an important impact on human health. This chapter focuses on its potential effect on cancer therapy, especially for chemotherapeutics with anthracyclines.


Assuntos
Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial/genética , Antraciclinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Alcoolismo/genética , Humanos
3.
Expert Opin Drug Metab Toxicol ; 15(7): 553-564, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162983

RESUMO

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects. Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD. Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.


Assuntos
Alcoolismo/tratamento farmacológico , Farmacogenética , Medicina de Precisão/métodos , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/efeitos adversos , Alcoolismo/genética , Alcoolismo/fisiopatologia , Humanos , Uso Off-Label
4.
Gene ; 707: 30-35, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31055022

RESUMO

BACKGROUND: Alcohol intake and tobacco smoking have significant negative health consequences and both are influenced by genetic predispositions. Some studies suggest that the FTO gene is associated with alcohol consumption. We investigated whether a tagging variant (rs17817449) within the FTO gene is associated with alcohol intake, problem drinking and smoking behaviour. METHODS: We analysed data from 26,792 Caucasian adults (47.2% of males; mean age 58.9 (±7.3) years), examined through the prospective cohort HAPIEE study. The primary outcomes were daily alcohol consumption, binge drinking, problem drinking (CAGE score 2+) and smoking status in relation to tagging variants within the FTO and ADH1B genes. RESULTS: We found no significant association of the FTO polymorphism with smoking status in either sex. The associations of the FTO polymorphism with drinking pattern were inconsistent and differed by gender. In men, GG homozygote carriers had lower odds of problem drinking (OR 0.85, 95% CI 0.75-0.96, p = 0.03). In women, the combination of the FTO/ADH1B GG/+A genotypes doubled the risk of binge drinking (OR 2.10, 95% CI 1.19-3.71, p < 0.05), and the risk was further increased among smoking women (OR 4.10, 95% CI 1.64-10.24, p = 0.008). CONCLUSIONS: In this large population study, the FTO gene appeared associated with binge and problem drinking, and the associations were modified by sex, smoking status and the ADH1B polymorphism.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Bebedeira/genética , Polimorfismo de Nucleotídeo Único , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Fumar/genética
5.
Nat Commun ; 10(1): 1499, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940813

RESUMO

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
6.
Mol Biol (Mosk) ; 53(1): 74-83, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30895954

RESUMO

This work studied the changes in the levels of the main proteins of the calpain system (µ-calpain, Ca^(2+)-dependent protease, and fragments of its autolysis, inhibitor calpastatin) and µ-calpain substrates (giant proteins of the sarcomere cytoskeleton, titin and nebulin) in skeletal muscle (m. gastrocnemius, m. soleus, m. longissimus dorsi) of rats alcoholized for three months by different methods using agar containing 30% ethanol and nutrient-balanced liquid feed containing 5% ethanol using gel electrophoresis methods under denaturing conditions and immunoblotting. No decrease in the muscle mass/body weight ratio, indicating the development of atrophy, no increase in autolysis of µ-calpain, indicating an increase in the activity of this enzyme, no changes in the content of intact titin (T1), nebulin, µ-calpain and calpastatin, as well as the total calpain activity measured using Calpain Activity Assay Kit were detected in alcoholized rats of both groups. No changes in the total level of titin phosphorylation in the rat muscles of alcoholized groups were detected using Pro-Q Diamond fluorescent dye for phosphate groups of proteins. No statistically significant differences in the content of titin and nebulin mRNA in skeletal muscles of control rats and rats alcoholized using agar were detected. In rats, alcoholized by the method of liquid feed, the levels of titin and nebulin mRNA were increased 1.5-2.5 times possibly due to a higher fat content in such a diet. The presented data may be useful for choosing a chronic alcoholization model for animals.


Assuntos
Alcoolismo/genética , Conectina/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Animais , Modelos Animais de Doenças , Ratos
7.
Drug Alcohol Depend ; 197: 271-279, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875648

RESUMO

BACKGROUND: Co-morbid substance use is very common. Despite a historical focus using genetic epidemiology to investigate comorbid substance use and misuse, few studies have examined substance-substance associations using polygenic risk score (PRS) methods. METHODS: Using summary statistics from the largest substance use GWAS to date (258,797- 632,802 subjects), GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), we constructed PRSs for smoking initiation (PRS-SI), age of initiation of regular smoking (PRS-AI), cigarettes per day (PRS-CPD), smoking cessation (PRS-SC), and drinks per week (PRS-DPW). We then estimated the fixed effect of individual PRSs on 22 lifetime substance use and substance use disorder phenotypes collected in an independent sample of 2463 young Australian adults using genetic restricted maximal likelihood (GREML) in Genome-wide Complex Trait Analysis (GCTA), separately in females, males and both sexes together. RESULTS: After accounting for multiple testing, PRS-SI significantly explained variation in the risk of cocaine (0.67%), amphetamine (1.54%), hallucinogens (0.72%), ecstasy (1.66%) and cannabis initiation (0.97%), as well as DSM-5 alcohol use disorder (0.72%). PRS-DPW explained 0.75%, 0.59% and 0.90% of the variation of cocaine, amphetamine and ecstasy initiation respectively. None of the 22 phenotypes including emergent classes of substance use were significantly predicted by PRS-AI, PRS-CPD, and PRS-SC. CONCLUSIONS: To our knowledge, this is the first study to report significant genetic overlap between the polygenic risks for smoking initiation and alcohol consumption and the risk of initiating major classes of illicit substances. PRSs constructed from large discovery GWASs allows the detection of novel genetic associations.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Herança Multifatorial , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Uso de Tabaco/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/epidemiologia , Alcoolismo/genética , Austrália/epidemiologia , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Fatores de Risco , Fumar/epidemiologia , Fumar/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Uso de Tabaco/genética , Adulto Jovem
9.
Transl Psychiatry ; 9(1): 71, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718457

RESUMO

A limited number of genetic variants have been identified in traditional GWAS as risk or protective factors for alcohol use disorders (AUD) and related phenotypes. We herein report whole-genome association and rare-variant analyses on AUD traits in American Indians (AI) and European Americans (EA). We evaluated 742 AIs and 1711 EAs using low-coverage whole-genome sequencing. Phenotypes included: (1) a metric based on the occurrence of 36 alcohol-related life events that reflect AUD severity; (2) two alcohol-induced affective symptoms that accompany severe AUDs. We identified two new loci for alcohol-related life events with converging evidence from both cohorts: rare variants of K2P channel gene KCNK2, and rare missense and splice-site variants in pro-inflammatory mediator gene PDE4C. A NAF1-FSTL5 intergenic variant and an FSTL5 variant were respectively associated with alcohol-related life events in AI and EA. PRKG2 of serine/threonine protein kinase family, and rare variants in interleukin subunit gene EBI3 (IL-27B) were uniquely associated with alcohol-induced affective symptoms in AI. LncRNA LINC02347 on 12q24.32 was uniquely associated with alcohol-induced depression in EA. The top GWAS findings were primarily rare/low-frequency variants in AI, and common variants in EA. Adrenal gland was the most enriched in tissue-specific gene expression analysis for alcohol-related life events, and nucleus accumbens was the most enriched for alcohol-induced affective states in AI. Prefrontal cortex was the most enriched in EA for both traits. These studies suggest that whole-genome sequencing can identify novel, especially uncommon, variants associated with severe AUD phenotypes although the findings may be population specific.


Assuntos
Sintomas Afetivos/genética , Alcoolismo/genética , Grupo com Ancestrais do Continente Europeu/genética , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Índios Norte-Americanos/genética , Sequenciamento Completo do Genoma , Adulto , Sintomas Afetivos/etiologia , Alcoolismo/complicações , Estudos de Coortes , Humanos , Índice de Gravidade de Doença , Estados Unidos
10.
Transl Psychiatry ; 9(1): 34, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728347

RESUMO

Adolescent alcohol drinking is known to contribute to the development and severity of alcohol use disorders (AUDs) later in adulthood. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical for brain development and synaptic plasticity. One such lncRNA is natural occurring brain-derived neurotrophic factor antisense (BDNF-AS) that has been shown to regulate BDNF expression. The role of BDNF-AS lncRNA in the molecular mechanisms of AUD is unknown. Here, we evaluated the expression and functional role of BDNF-AS in postmortem amygdala of either early onset or late onset alcoholics (individuals who began drinking before or after 21 years of age, respectively) and age-matched control subjects. BDNF-AS expression is increased in early onset but not in late onset AUD amygdala and appears to be regulated epitranscriptomically via decreased N6-methyladenosine on BDNF-AS. Upregulation of BDNF-AS is associated with a significant decrease in BDNF expression and increased recruitment of EZH2, which deposits repressive H3K27 trimethylation (H3K27me3) at regulatory regions in the BDNF gene in the early onset AUD group. Drinking during adolescence also contributed to significant decreases in activity-regulated cytoskeleton-associated protein (ARC) expression which also appeared to be mediated by increased EZH2 deposition of repressive H3K27me3 at the ARC synaptic activity response element. These results suggest an important role for BDNF-AS in the regulation of synaptic plasticity via epigenetic reprogramming in the amygdala of AUD subjects who began drinking during adolescence.


Assuntos
Alcoolismo/genética , Tonsila do Cerebelo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , RNA Longo não Codificante/metabolismo , Estudos de Casos e Controles , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , RNA Longo não Codificante/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-30677468

RESUMO

OBJECTIVE: Alcohol use disorders inflict a great individual and societal burden. Although sex hormone effects have been implicated in alcohol dependence, research has mostly neglected estrogen activities and female alcohol-dependent patients. Here, we investigated associations of estrogen receptor 1 (ESR1) genetics and serum estradiol activities with aspects of alcohol dependence. METHOD: Serum estradiol activities of early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) were followed for at median 5 days and compared with healthy controls (n[♂] = 133, n[♀] = 107). All participants were genotyped for five ESR1 single nucleotide polymorphisms (rs6902771, rs11155819, rs6557171, rs2982683, rs2982712). RESULTS: Bioavailable estradiol levels decreased during withdrawal treatment (P[♂] < .001, P[♀] = .011). Male patients with an increase of bioavailable estradiol during withdrawal showed fewer days to (P = .033) and more alcohol-related readmissions (P < .05) during the 12-month follow-up. Higher estradiol and estradiol-to-testosterone activities were significantly related to liver, muscle, and cell count damage in male patients. Estradiol-to-testosterone activities in female patients were lower compared to female controls (total P = .013, bioavailable P = .009). Moreover, the ESR1 genotypes jointly separated alcohol-dependent patients from controls (P = .037). CONCLUSION: Our findings support the role of ESR1 genetics in alcohol dependence and show for the first time that estradiol activities may sex-specifically predict alcohol-related sequelae and outcome following in-patient withdrawal treatment.


Assuntos
Alcoolismo/genética , Estradiol/sangue , Receptor alfa de Estrogênio/genética , Adulto , Alcoolismo/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Caracteres Sexuais , Síndrome de Abstinência a Substâncias/sangue , Testosterona/sangue
12.
PLoS One ; 14(1): e0210546, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629674

RESUMO

BACKGROUND: The presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field. METHODS: Using multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women. RESULTS: DIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82-32.4] and 9.89 [3.50-27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18-7.38] and 3.79 [1.40-10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02-1.35] and 1.38 [1.14-1.67]), and a mean corpuscular volume ≥106 fl (3.70 [1.56-8.81] and 3.27 [1.24-8.64]) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 [10.6-146]). CONCLUSIONS: Japanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.


Assuntos
Álcool Desidrogenase/genética , Alcoolismo/complicações , Alcoolismo/genética , Aldeído-Desidrogenase Mitocondrial/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Adulto , Idoso , Alcoolismo/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Endoscopia Gastrointestinal , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Esôfago/metabolismo , Esôfago/patologia , Feminino , Genótipo , Humanos , Iodo/análise , Japão/epidemiologia , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Fatores Sexuais , Coloração e Rotulagem
13.
Transl Psychiatry ; 9(1): 32, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670680

RESUMO

Similar environmental risk factors have been implicated in different neuropsychiatric disorders (including major psychiatric and neurodegenerative diseases), indicating the existence of common epigenetic mechanisms underlying the pathogenesis shared by different illnesses. To investigate such commonality, we applied an unsupervised computational approach identifying several consensus co-expression and co-methylation signatures from a data cohort of postmortem prefrontal cortex (PFC) samples from individuals with six different neuropsychiatric disorders-schizophrenia, bipolar disorder, major depression, alcoholism, Alzheimer's and Parkinson's-as well as healthy controls. Among our results, we identified a pair of strongly interrelated co-expression and co-methylation (E-M) signatures showing consistent and significant disease association in multiple types of disorders. This E-M signature was enriched for interneuron markers, and we further demonstrated that it is unlikely for this enrichment to be due to varying subpopulation abundance of normal interneurons across samples. Moreover, gene set enrichment analysis revealed overrepresentation of stress-related biological processes in this E-M signature. Our integrative analysis of expression and methylation profiles, therefore, suggests a stress-related epigenetic mechanism in the brain, which could be associated with the pathogenesis of multiple neuropsychiatric diseases.


Assuntos
Alcoolismo/genética , Doença de Alzheimer/genética , Transtorno Bipolar/genética , Metilação de DNA , Transtorno Depressivo Maior/genética , Doença de Parkinson/genética , Esquizofrenia/genética , Epigênese Genética , Redes Reguladoras de Genes , Humanos
14.
Behav Genet ; 49(1): 11-23, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30536213

RESUMO

A statistical mediation model was developed within a twin design to investigate the etiology of alcohol use disorder (AUD). Unlike conventional statistical mediation models, this biometric mediation model can detect unobserved confounding. Using a sample of 1410 pairs of Norwegian twins, we investigated specific hypotheses that DSM-IV personality-disorder (PD) traits mediate effects of childhood stressful life events (SLEs) on AUD, and that adulthood SLEs mediate effects of PDs on AUD. Models including borderline PD traits indicated unobserved confounding in phenotypic path coefficients, whereas models including antisocial and impulsive traits did not. More than half of the observed effects of childhood SLEs on adulthood AUD were mediated by adulthood antisocial and impulsive traits. Effects of PD traits on AUD 5‒10 years later were direct rather than mediated by adulthood SLEs. The results and the general approach contribute to triangulation of developmental origins for complex behavioral disorders.


Assuntos
Alcoolismo/etiologia , Transtornos da Personalidade/genética , Adulto , Experiências Adversas da Infância , Alcoolismo/genética , Biometria , Criança , Manual Diagnóstico e Estatístico de Transtornos Mentais , Doenças em Gêmeos , Feminino , Interação Gene-Ambiente , Humanos , Acontecimentos que Mudam a Vida , Masculino , Modelos Estatísticos , Noruega , Personalidade , Transtornos da Personalidade/complicações , Fenótipo , Fatores de Risco , Gêmeos/genética , Gêmeos/psicologia
16.
Mutat Res ; 777: 19-28, 2018 Jul - Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30115428

RESUMO

DNA sequence is a powerful tool that can be used for an individual's identification and investigation of various abnormalities in the genome. However, recent studies have identified other heritable changes by epigenetic mechanisms that cause changes in gene expression without altering the DNA sequence itself. In particular, DNA methylation mediates long-lasting changes in gene promoters, which makes it an appealing epigenetic mechanism to study variation in methylation status that characterizes the extent of drug abuse. We summarize recent findings on methylation alterations in a number of genes caused by various drugs including cocaine, opioids, cannabinoids, amphetamine, phenobarbital, and alcohol in various human and animal model studies. Additionally, a minimal discussion of the basic concepts of methylation is provided. The determination of possible DNA methylation alterations can assist in finding the cause and circumstances of death or ailment, and gene markers can be potentially used as biomarkers in the future.


Assuntos
Alcoolismo/genética , Metilação de DNA , Transtornos Relacionados ao Uso de Substâncias/genética , Animais , Biomarcadores , Transtornos Relacionados ao Uso de Cocaína/genética , Ilhas de CpG , Epigênese Genética , Humanos , Transtornos Relacionados ao Uso de Opioides/genética , Regiões Promotoras Genéticas
17.
Drug Alcohol Depend ; 189: 178-186, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30049530

RESUMO

While there is developing research on how genes moderate the effect of stressful life events on substance use, the limited research has yet to focus on specific stressors. As adolescent dating violence victimization has been linked to various substance use behaviors, the current research seeks to further examine the longitudinal outcomes of adolescent dating violence victimization and the role that genes play in moderating these effects. Specifically, using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a series of logistic and negative binomial regressions are run to analyze the direct and interactive effects of adolescent dating violence victimization and a polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene on both alcohol use problems and marijuana use. The results find that 5HTTLPR interacts with adolescent dating violence victimization to increase odds of marijuana use for the sample. However, the interaction between 5HTTLPR and adolescent dating violence has differential effects for males and females, suggesting sex differences regarding the susceptibility properties of 5HTTLPR. Implications of these findings are discussed.


Assuntos
Comportamento do Adolescente/psicologia , Alcoolismo/genética , Vítimas de Crime , Interação Gene-Ambiente , Violência por Parceiro Íntimo , Uso da Maconha/genética , Polimorfismo Genético/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Adulto Jovem
18.
Fa Yi Xue Za Zhi ; 34(2): 142-146, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29923378

RESUMO

OBJECTIVES: To explore the effects of ADH1B and ALDH2 gene polymorphism and type of alcoholic beverage on ethanol metabolism, to provide data support for cases involving the interpretation of ethanol metabolism or back calculation of blood ethanol concentration in forensic practice. METHODS: A total of 81 volunteers were selected. The genotypes of ADH1B, ADH1C and ALDH2 were obtained by a multiplex SNaPshot genotyping method. Each subject was administered with 1.0 g/kg of alcohol. About 1 mL venous blood was collected before and after the alcohol consumption at 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h and 8 h, respectively. The concentrations of ethanol and acetaldehyde in blood were determined by headspace gas chromatography. The peak times of blood ethanol concentration (Tmax), the peak mass concentrations of ethanol (Cmax), the area under curve (AUC) of ethanol (AUCethanol), AUCacetaldehyde and ethanol elimination rates (ß) were calculated. In order to eliminate the influence of ADH1C, the ADH1C*1/*1 carriers were grouped based on the genotype of ADH1B and ALDH2. The data of each group were evaluated by one-way analysis of variance and pairwise comparison tests were performed by least significant difference method. The gene interactions were evaluated by two-way analysis of variance. Each parameter of three kinds of alcoholic beverage (white wine, red wine and beer) among groups was analysed by variance analysis with randomized block design. RESULTS: There were no differences in the value of Tmax and Cmax between the groups with different ADH1B and ALDH2 genotype. The differences in the values of AUCethanol, ß and AUCacetaldehyde among some groups carrying different ADH1B and ALDH2 genotype had statistical significance, while no significant difference was observed in these parameters when one individual taking same dose of different alcoholic beverage type. CONCLUSIONS: The ethanol metabolism is associated with the related gene polymorphism, which is barely affected by alcoholic beverage type.


Assuntos
Álcool Desidrogenase/genética , Alcoolismo/genética , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Acetaldeído/sangue , Álcool Desidrogenase/metabolismo , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/etnologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Bebidas Alcoólicas , Alcoolismo/epidemiologia , Alcoolismo/etnologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , China/epidemiologia , Etanol/administração & dosagem , Etanol/sangue , Frequência do Gene/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino
19.
Environ Toxicol Pharmacol ; 62: 30-39, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29940492

RESUMO

We evaluated genetic variability of single nucleotide polymorphisms (SNPs) situated in the CYP2E1 gene promoter in alcoholics. We also compared 1000 Genomes Project of CYP2E1 polymorphisms with frequencies of genotypes and haplotypes. Eight variation points were exclusively found in Brazilians. The allelic distributions of the rs3813867, rs2031920 and rs2031921 polymorphisms in the CYP2E1 showed that the wild alleles (G, C, T, respectively) had higher frequencies in both groups, alcoholic (96%, 96%, 96%) and a control group (95.8%, 94.9%, 94.9%), when compared to the mutated allele (C, T, C, respectively). The variation points, rs3813867, rs2031920 and rs2031921 showed strong linkage disequilibrium (LOD ≥ 2, D ' = 1). South Asian populations presented larger LD blocks compared to the other populations. Our results showed that the allelic frequencies were markedly different among ethnicities and have contributed to the knowledge regarding the distribution among ethnic groups, being associated to alcohol consumption worldwide.


Assuntos
Alcoolismo/genética , Citocromo P-450 CYP2E1/genética , Brasil , Grupos Étnicos/genética , Genoma Humano , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
20.
Science ; 360(6395): 1321-1326, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29930131

RESUMO

Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.


Assuntos
Alcoolismo/metabolismo , Tonsila do Cerebelo/metabolismo , Comportamento Aditivo/metabolismo , Comportamento de Escolha , Etanol/efeitos adversos , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Recompensa , Alcoolismo/genética , Alcoolismo/fisiopatologia , Tonsila do Cerebelo/fisiopatologia , Animais , Comportamento Aditivo/genética , Comportamento Aditivo/fisiopatologia , Regulação para Baixo , Etanol/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Técnicas de Silenciamento de Genes , Humanos , Locomoção , Masculino , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Sacarina/administração & dosagem , Transcrição Genética
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