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1.
Int. j. morphol ; 38(3): 616-621, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098296

RESUMO

The chronic consumption of alcohol causes a worsening of the events that follow the cerebral ischemia. These events are regulated through the expression of several genes and microRNAs. The aimof this work was To analyze and describe the expression profile of PARP and AIF and miRNA-9 proteins in rats submitted to focal cerebral ischemia, associated or not with chronic alcoholism model. Methods: Twenty adult Wistar rats, subdivided into: control; ischemic; alcoholic and ischemic / alcoholized for immunohistochemical analysis and miRNA-9 gene expression. Results: There was a reduction in the protein expression of PARP-1 and a positive marking for AIF in the ischemic / alcoholized group. The miRNA-9 did not obtain significant expression. The association of ischemia with chronic alcohol use promoted a tendency to low expression of miRNA-9, low expression of PARP-1 and high expression of AIF, indicating an interference in the protective effect of miRNA-9 be observed in the other groups.


El consumo crónico de alcohol provoca un empeoramiento de los eventos que siguen a la isquemia cerebral. Estos eventos están regulados a través de la expresión de varios genes y microRNA. El objetivo de este trabajo fue analizar y describir el perfil de expresión de las proteínas PARP y AIF y microRNA-9 en ratas sometidas a isquemia cerebral focal, asociadas o no, con el modelo de alcoholismo crónico. Veinte ratas Wistar adultas se dividieron en: grupo control, isquémico alcohólico, e isquémico / alcoholizado para análisis inmunohistoquímico y expresión de genes microRNA-9. Resultados: Hubo una reducción en la expresión de proteínas de PARP-1 y un marcado positivo para AIF en el grupo isquémico / alcoholizado. No se observó una expresión significativa en el microRNA-9. La asociación de la isquemia con el consumo crónico de alcohol promovió una tendencia a la baja expresión de microRNA-9, baja expresión de PARP1 y alta expresión de AIF, lo que indica una interferencia en el efecto protector de microRNA-9 en los otros grupos.


Assuntos
Animais , Ratos , Isquemia Encefálica/metabolismo , Alcoolismo/metabolismo , Imuno-Histoquímica , Isquemia Encefálica/genética , Ratos Wistar , MicroRNAs/metabolismo , Modelos Animais de Doenças , Alcoolismo/genética , Fator de Indução de Apoptose/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo
2.
Biomed Khim ; 66(3): 208-215, 2020 May.
Artigo em Russo | MEDLINE | ID: mdl-32588826

RESUMO

Alcohol use is a global socially significant problem that remains one of the leading risk factors for disability and premature death. One of the main pathological characteristics of alcoholism is the loss of cognitive control over the amount of consumed alcohol. Growing body of evidence suggests that alterations of neuroimmune communication occurring in the brain during prolonged alcoholization are one of the main mechanisms responsible for the development of this pathology. Ethanol consumption leads to activation of neuroimmune signaling in the central nervous system through many types of Toll-like receptors (TLRs), as well as the release of their endogenous agonists (HMGB1 protein, S100 protein, heat shock proteins, extracellular matrix breakdown proteins). Activation of TLRs triggers intracellular molecular cascades leading to increased expression of the innate immune system genes, particularly proinflammatory cytokines, subsequently causing the development of a persistent neuroinflammatory process in the central nervous system, which results in massive death of neurons and glial cells in the brain structures, which are primarily associated with the development of a pathological craving for alcohol. In addition, some subtypes of TLRs are capable of forming heterodimers with neuropeptide receptors (corticoliberin, orexin, ghrelin receptors), and may also have other functional relationships.


Assuntos
Alcoolismo , Proteína HMGB1 , Receptores Toll-Like , Alcoolismo/genética , Alcoolismo/imunologia , Etanol , Proteína HMGB1/genética , Humanos , Neuroimunomodulação , Receptores Toll-Like/genética
3.
PLoS One ; 15(5): e0233319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469986

RESUMO

Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microarray and scale-free network analysis of expression responses in a C57BL/6J mouse model utilizing chronic intermittent ethanol by vapor chamber (CIE) in combination with limited access oral ethanol consumption. This model has previously been shown to produce long-lasting increased ethanol consumption, particularly when combining oral ethanol access with repeated cycles of intermittent vapor exposure. The interaction of CIE and oral consumption was studied by expression profiling and network analysis in medial prefrontal cortex, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain region expression networks were analyzed for ethanol-responsive gene expression, correlation with ethanol consumption and functional content using extensive bioinformatics studies. In all brain-regions studied the largest number of changes in gene expression were seen when comparing ethanol naïve mice to those exposed to CIE and drinking. In the prefrontal cortex, however, unique patterns of gene expression were seen compared to other brain-regions. Network analysis identified modules of co-expressed genes in all brain regions. The prefrontal cortex and nucleus accumbens showed the greatest number of modules with significant correlation to drinking behavior. Across brain-regions, however, many modules with strong correlations to drinking, both baseline intake and amount consumed after CIE, showed functional enrichment for synaptic transmission and synaptic plasticity.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversos , Alcoolismo/etiologia , Alcoolismo/patologia , Animais , Encéfalo/patologia , Biologia Computacional , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transmissão Sináptica
4.
Nat Neurosci ; 23(7): 809-818, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451486

RESUMO

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Consumo de Bebidas Alcoólicas/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial
5.
Minerva Med ; 111(4): 344-353, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32338485

RESUMO

Nowadays harmful alcohol consumption represents one of the most important risk factors for the development of several type of chronic and acute diseases in the western countries, contributing to a great number of deaths. Focusing the attention on cancer development and progression, the scientific community has a large consensus in declaring the existence of a harmful association between alcohol consumption and liver, breast, upper aerodigestive tract (mouth, oropharynx, hypopharynx, and esophagus), pancreas and colon cancer appearance. However the precise biological links by which the alcohol could be responsible for cancer initiation and progression are not fully understood yet, even if the International Agency for Research on Cancer (IARC) indicated both ethanol and acetaldehyde as carcinogen for humans. The possible explanation of the effect exerted by ethanol and acetaldehyde could be related to direct genotoxicity, hormonal disturbance, triggering of oxidative stress and inflammation. In this review, we examine the relationship between alcohol dosage and associated diseases, with focus on alcohol-related cancers. Furthermore, to understand the potential molecular mechanisms of these diseases, the results of in vivo experiments on animal models were discussed.


Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo/diagnóstico , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/complicações , Alcoolismo/genética , Animais , Modelos Animais de Doenças , Etanol/administração & dosagem , Humanos , Neoplasias/etiologia , Polimorfismo Genético
6.
Tohoku J Exp Med ; 250(2): 109-119, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32115493

RESUMO

Colorectal cancer is the third cause of cancer and the second leading cause of death worldwide. The CD44 gene plays a key role in malignant processes, including growth, survival, epithelial to mesenchymal transition and metastasis. It is also known that some variants as rs187116 (c.67+4883G>A) and rs7116432 (c.2024+779A>G) can modulate the function of the CD44 gene and malignant transformation in several neoplasms. This study aims to explore, for the first time, the association of the CD44 rs187116 and rs7116432 variants in patients with colorectal cancer. Genomic DNA from 250 patients and 250 healthy blood donors were analyzed. The identification of variants was made by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) test and multivariate analysis. Individuals carrying the G/A and A/A genotypes for the rs187116 polymorphism showed an increased risk for colorectal cancer (OR = 3.11, 95% CI: 1.87-5.16, P = 0.001 and OR = 3.59, 95% CI: 2.06-6.25, P = 0.001, respectively). After adjusting for age and gender, these same genotypes and the G/G genotype of the rs7116432 polymorphism were associated with TNM stage and tumor location in the colon. Moreover, the A-G (rs187116 and rs7116432) haplotype was associated with increased risk; while, the haplotype G-A (rs187116 and rs7116432) was related with decreased risk. In conclusion, our results suggest that the here analyzed CD44 variants are involved with risk, TNM stage and tumor location in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Hialuronatos/genética , Fatores Etários , Alcoolismo/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Análise Multivariada , Estadiamento de Neoplasias , Polimorfismo de Fragmento de Restrição , Fumar/genética
7.
Exp Clin Psychopharmacol ; 28(4): 379-387, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32150428

RESUMO

Alcohol consumption may precede, or result from, behavioral inflexibility and contribute to individuals' difficulties ceasing drinking. Attentional set shifting tasks are an animal analog to a human behavioral flexibility task requiring recognition of a previous strategy as inappropriate, and the formation and maintenance of a novel strategy (Floresco, Block, & Tse, 2008). Abstinent individuals with alcohol use disorder, nonalcoholic individuals with a family history of alcoholism, and mice exposed to chronic-intermittent alcohol vapor show impaired behavioral flexibility (Gierski et al., 2013; Hu, Morris, Carrasco, & Kroener, 2015; Oscar-Berman et al., 2009). Behavioral flexibility deficits can be linked to frontal cortical regions connected to the striatum (Ragozzino, 2007), and alterations to the endocannabinoid system, implicated in drug seeking and consumption (Economidou et al., 2006; Serrano & Parsons, 2011), may affect these behaviors. Alcohol-preferring and nonpreferring rodents exhibit differences in CB1 receptor expression (CB1R; Hansson et al., 2007; Hungund & Basavarajappa, 2000), but whether dorsal striatal CB1Rs are important for other alcohol-related behaviors such as attentional set shifting tasks remains unclear. This study assesses whether selectively bred high (HAP) versus low alcohol-preferring mice differ in an operant attentional set shifting task or CB1R levels in the dorsal striatum and whether a history of voluntary alcohol consumption in crossed HAP mice exacerbates inflexibility. Contrary to our hypothesis, neither genetic differences in alcohol preference nor drinking affected set shifting. However, high alcohol-preferring mice-3 mice showed reduced levels of dorsal striatal CB1R compared with low alcohol-preferring-3 mice, suggesting that genetic differences in alcohol consumption may be mediated in part by striatal CB1R. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Etanol/administração & dosagem , Animais , Atenção , Feminino , Masculino , Camundongos
8.
BMC Med Genomics ; 13(Suppl 3): 19, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093702

RESUMO

BACKGROUND: The current understanding of the genetic basis of complex human diseases is that they are caused and affected by many common and rare genetic variants. A considerable number of the disease-associated variants have been identified by Genome Wide Association Studies, however, they can explain only a small proportion of heritability. One of the possible reasons for the missing heritability is that many undiscovered disease-causing variants are weakly associated with the disease. This can pose serious challenges to many statistical methods, which seems to be only capable of identifying disease-associated variants with relatively stronger coefficients. RESULTS: In order to help identify weaker variants, we propose a novel statistical method, Constrained Sparse multi-locus Linear Mixed Model (CS-LMM) that aims to uncover genetic variants of weaker associations by incorporating known associations as a prior knowledge in the model. Moreover, CS-LMM accounts for polygenic effects as well as corrects for complex relatednesses. Our simulation experiments show that CS-LMM outperforms other competing existing methods in various settings when the combinations of MAFs and coefficients reflect different scenarios in complex human diseases. CONCLUSIONS: We also apply our method to the GWAS data of alcoholism and Alzheimer's disease and exploratively discover several SNPs. Many of these discoveries are supported through literature survey. Furthermore, our association results strengthen the belief in genetic links between alcoholism and Alzheimer's disease.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Estatística como Assunto/métodos , Adulto , Alcoolismo/genética , Algoritmos , Doença de Alzheimer/genética , Simulação por Computador , Feminino , Variação Genética , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
9.
Pharmacogenet Genomics ; 30(3): 54-60, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32084087

RESUMO

OBJECTIVE: This study sought to evaluate the impacts of interactions between the alcohol dehydrogenase-1B (rs1229984) genotype and the aldehyde dehydrogenase-2 (rs671) genotype on alcohol flushing, alcohol reeking on the day after drinking, and the age distribution in alcohol-dependent patients. METHODS: The study subjects were 4107 Japanese alcohol-dependent men who underwent alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotyping: 4051 patients were asked about their current or former tendency to experience facial flushing after drinking a glass of beer, and 969 patients were asked about whether they had ever been told that they reeked of alcohol more than 12 hours after they had stopped drinking. RESULTS: Current, former, and never flushing were reported in 3.5, 14.9, and 81.5%, respectively, of the subject, and alcohol reeking after more than 12 hours in 36.1% of the subjects. The fast-metabolizing ADH1B*2(+) genotype (*1/*2 or *2/*2) and the inactive ALDH2*2(+) genotype (*1/*2 or *2/*2) affected the multivariate odds ratios for current or former flushing [odds ratio, 95% confidence interval = 2.27 (1.79-2.86) and 23.0 (18.6-28.5), respectively, vs. *2(-) genotype] and for alcohol reeking [0.39 (0.29-0.52) and 1.56 (1.09-2.25), respectively, vs. *2(-) genotype]. An age-dependent decrease in the ADH1B*2(-) and ALDH2*2(-) combination from 32.3% in the 30-39-year age group to 12.5% in the 70-79-year age group and an age-dependent increase in the ADH1B*2(+) and ALDH2*2(-) combination from 52.5% in the 30-39-year age group to 70.5% in the 70-79-year age group were observed (P < 0.0001 for trend). The frequencies of the ADH1B*2(-) and ALDH2*2(+) combination (4.7-6.2%) and the ADH1B*2(+) and ALDH2*2(+) combination (8.9-12.0%) did not change markedly with increasing age. CONCLUSION: Interactions between the alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes modified alcohol flushing, alcohol reeking on the day after drinking, and the age distribution. These findings support the protective roles of the ADH1B*2(+) and ALDH2*2(+) genotypes against the development of alcohol dependence.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Aldeído-Desidrogenase Mitocondrial/genética , Rubor/genética , Adulto , Distribuição por Idade , Idoso , Álcool Desidrogenase/sangue , Aldeído-Desidrogenase Mitocondrial/sangue , Estudos de Associação Genética , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Análise de Regressão , Inquéritos e Questionários
10.
Sci Rep ; 10(1): 2451, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051453

RESUMO

Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45+ cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Alcoolismo/patologia , Hepatopatias Alcoólicas/patologia , Fígado/patologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/imunologia , Alcoolismo/etiologia , Alcoolismo/genética , Alcoolismo/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Humanos , Fígado/imunologia , Fígado/metabolismo , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma
11.
Nat Commun ; 11(1): 512, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980605

RESUMO

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that INa is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Neurônios/metabolismo , Nó Sinoatrial/fisiopatologia , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Adulto , Idoso , Alcoolismo/genética , Arritmias Cardíacas/genética , Doença Crônica , Simulação por Computador , Feminino , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/metabolismo , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Imagem Óptica , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Nó Sinoatrial/metabolismo , Canais de Sódio/genética , Estresse Fisiológico , Adulto Jovem
12.
Eur Addict Res ; 26(2): 85-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940649

RESUMO

BACKGROUND: Alcohol use disorder (AUD) is to a high degree heritable, and in clinical practice it is common to assert presence of alcohol abuse family history (FH) in treatment-seeking AUD patients. Patients with AUD also exhibit cognitive deficits, including elevated impulsivity and impairments in executive functions (EF), but less is known regarding the relation between FH and these cognitive domains. The aim of the current study was to investigate if alcohol abuse FH in AUD patients is associated with a specific cognitive profile. METHODS: Patients with AUD (n = 197) from Sweden (n = 106) and Belgium (n = 91) were recruited. Self-rated impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). EF assessed were response inhibition (stop signal task), attention (rapid visual processing task), and working memory (digit span). A series of linear regression models were run to explore the effect of FH on cognitive outcomes. RESULTS: A FH of alcohol abuse was associated with elevated score in self-rated impulsivity assessed by the BIS, with the greatest effect on the subscale of nonplanning. There was no statistically significant association between FH and any of the other neuropsychological task outcomes. CONCLUSION: Presence of alcohol abuse FH within AUD patients could be a marker of higher impulsivity, which may have clinical implications regarding diagnostic evaluation and treatment.


Assuntos
Transtornos Relacionados ao Uso de Álcool/genética , Alcoolismo/genética , Comportamento Impulsivo/fisiologia , Anamnese , Adulto , Alcoolismo/psicologia , Bélgica , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Suécia
13.
Sci Adv ; 6(3): eaay5034, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998841

RESUMO

High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Biomarcadores , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transdução de Sinais
14.
Pharmacogenomics ; 21(2): 111-123, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31957548

RESUMO

Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.


Assuntos
Alcoolismo/genética , Transtornos de Ansiedade/tratamento farmacológico , Benzodiazepinas/administração & dosagem , Citocromo P-450 CYP2C19/genética , Adulto , Alcoolismo/patologia , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/patologia , Benzodiazepinas/efeitos adversos , Feminino , Genótipo , Humanos , Masculino
15.
Curr Top Behav Neurosci ; 47: 93-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31845132

RESUMO

Externalizing problems generally refer to a constellation of behaviors and/or disorders characterized by impulsive action and behavioral disinhibition. Phenotypes on the externalizing spectrum include psychiatric disorders, nonclinical behaviors, and personality characteristics (e.g. alcohol use disorders, other illicit substance use, antisocial behaviors, risky sex, sensation seeking, among others). Research using genetic designs including latent designs from twin and family data and more recent designs using genome-wide data reveal that these behaviors and problems are genetically influenced and largely share a common genetic etiology. Large-scale gene-identification efforts have started to identify robust associations between genetic variants and these phenotypes. However, there is still considerable work to be done. This chapter provides an overview of the current state of research into the genetics of behaviors and disorders on the externalizing spectrum.


Assuntos
Alcoolismo , Transtornos Relacionados ao Uso de Substâncias , Alcoolismo/genética , Transtorno da Personalidade Antissocial/genética , Humanos , Comportamento Impulsivo , Fenótipo
16.
Proc Natl Acad Sci U S A ; 116(51): 25974-25981, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31792171

RESUMO

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- (Aldh2 -/-) and tissue-specific Aldh2-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior. Aldh2 -/- mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specific Aldh2 knockout (Aldh2 Hep-/-) mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed in Aldh2 -/- mice. Energy expenditure and motility were dramatically dampened in Aldh2 -/- mice, but moderately decreased in Aldh2 Hep-/- mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model, Aldh2 -/- mice drank negligible volumes from ethanol-containing bottles, whereas Aldh2 Hep-/- mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specific Aldh2 deficiency did not affect voluntary alcohol consumption. Finally, specific liver Aldh2 knockdown via injection of shAldh2 markedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepatic ALDH2 targeting/editing for the treatment of AUD.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Aldeído-Desidrogenase Mitocondrial/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Etanol/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Acetaldeído/metabolismo , Alanina Transaminase/sangue , Alcoolismo/genética , Alcoolismo/metabolismo , Animais , Quimiocina CCL2/metabolismo , Deleção de Genes , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroglia , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Transcriptoma
17.
Nat Commun ; 10(1): 5039, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745073

RESUMO

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10-6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Bancos de Espécimes Biológicos/estatística & dados numéricos , Casamento , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Reprodução/genética , Autorrelato , Reino Unido
18.
Turk Psikiyatri Derg ; 30(2): 82-89, 2019.
Artigo em Turco | MEDLINE | ID: mdl-31487373

RESUMO

OBJECTIVE: We planned to compare individuals with alcohol dependence (AD) and healthy controls on the frequency of NOS1 exon 1f-VNTR gene polymorphism and to investigate the effects of this polymorphism on the clinical symptoms of alcohol dependence, impulsiveness and comorbid attention deficit hyperactivity disorder (ADHD) symptoms. METHOD: A total of 282 participants consisting of 153 patients and 129 age and gender matched healthy individuals were inluded in the study. All participants were evaluated with Structured Clinical Interview for DSM-IV Axis 1 disorders (SCID-I) and Michigan Alcohol Screening Test (MAST), Barratt Impulsiveness Scale (BIS-11), UPPS Impulsive Behavior Scale, Adult Attention Deficit and Hyperactivity Diagnosis Scale (ADHDS), Family History Research Diagnostic Criteria (FHDRC). The QF-PCR fragment protocols were used for genetic analyses. Allele fragments of ≤176 bp and >176 bp sizes were separated and 3 different genotypes were determined as the SS, SL and LL. Associations of these genotypes with symptoms of AD severity, impulsiveness and comorbid ADHD were investigated. RESULTS: The AD and control groups did not differ significantly on the basis of NOS1 exon 1f-VNTR gene polymorphism. Also, significant correlations between this polymorphism and symptoms of AD severity, impulsiveness and ADHD were not determined. CONCLUSION: Results of our study do not indicatea significant association between the NOS1 exon 1f-VNTR genotypes and AD, subgroups of AD, impulsiveness or comorbid ADHD semptoms.


Assuntos
Alcoolismo/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Óxido Nítrico Sintase Tipo I/genética , Adolescente , Adulto , Idoso , Alcoolismo/complicações , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Estudos de Casos e Controles , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Comportamento Impulsivo , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
19.
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
20.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540133

RESUMO

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol intake represents a global health care burden. ALD encompasses a broad spectrum of hepatic injuries including asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The susceptibility of alcoholic patients to develop ALD is highly variable and its progression to more advanced stages is strongly influenced by several hits (i.e., amount and duration of alcohol abuse). Among them, the intestinal microbiota and its metabolites have been recently identified as paramount in ALD pathophysiology. Ethanol abuse triggers qualitative and quantitative modifications in intestinal flora taxonomic composition, mucosal inflammation, and intestinal barrier derangement. Intestinal hypermeability results in the translocation of viable pathogenic bacteria, Gram-negative microbial products, and pro-inflammatory luminal metabolites into the bloodstream, further corroborating the alcohol-induced liver damage. Thus, the premise of this review is to discuss the beneficial effect of gut microbiota modulation as a novel therapeutic approach in ALD management.


Assuntos
Alcoolismo/microbiologia , Microbioma Gastrointestinal/fisiologia , Hepatopatias Alcoólicas/microbiologia , Alcoolismo/genética , Alcoolismo/imunologia , Alcoolismo/fisiopatologia , Animais , Antibacterianos/efeitos adversos , Ácidos e Sais Biliares/metabolismo , Dieta , Suplementos Nutricionais/microbiologia , Disbiose/imunologia , Disbiose/metabolismo , Transplante de Microbiota Fecal , Hepatócitos/metabolismo , Humanos , Intestinos/microbiologia , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/fisiopatologia
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