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Haplotype block structure for the ALDH1A1 gene on chromosome 9. Haplotype blocks are outlined. Figures represent D′
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Alcohol dependence (AD) has a large heritable component. Genetic variation in genes involved in the absorption and elimination of ethanol have been associated with AD. However, some of these polymorphisms are not present in an African population. Previous studies have reported that a type of AD which is characterized by anxious behaviour may be a g...
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Background:
Colorectal cancer (CRC) is one of the most common cancers worldwide, and genetic variations exert distinct roles in its pathogenesis. Single nucleotide polymorphisms (SNPs) in interleukin 1 alpha (IL1A) were reported to be correlated to the susceptibility of diverse cancers. The aim of this study was to assess the association of IL1A S...
Citations
... A total of 101 participants in the trial were computed on the basis of the sampling performed in previous similar studies [24][25][26]. Male patients who met the diagnostic criteria for alcohol use disorder according to the ICD (International Classification of Diseases) 10 years of age to older than 35 years of age were enrolled. People with psychotic or bipolar disorders, dementia and liver diseases were excluded from the present study. ...
... Limitations may include a small sample size compared to previous studies [24][25][26]. Moreover, as expected for predominantly Caucasian samples [45,46], we found just a small number of individuals with the variant genotypes ADH1B*2, ADH1B*3 and ALDH2*2. ...
Background: The efficacy of naltrexone in the treatment of alcohol use disorder (AUD) has been associated with a set of variables not directly related with the expression of opioid receptors. All the variables have been found to be highly associated with AUD itself or more severe clinical levels of AUD. Objectives: Given the high association between alcohol metabolizing enzymes (AME) and the outcome of AUD, the present study aims to investigate the role of AME genotype variants in the treatment of AUD with naltrexone. Methods: We carried out a 12-week longitudinal clinical trial based on the treatment of AUD patients with naltrexone (N = 101), stratified by different alcohol metabolization genotypes. Genotyping was performed after the inclusion of the patients in the study, based on the individual presence of single nucleotide polymorphisms (SNPs) in the ADH (alcohol dehydrogenase)1B (ADH1B*2 and ADH1B*3), ADH1C (ADHC*1) and ALDH (aldehyde dehydrogenase) 2 (ALDH2*2) genes. The outcome of alcohol use has been monitored employing the timeline follow-back during the treatment. Results: The ADH1C*1 (Ile350Val, rs698) and ALDH2*2 (Glu504Lys, rs671) polymorphisms were associated with a better response to naltrexone treatment, whereas the ADH1B*3 (Arg370Cys, rs2066702) allelic variant showed a negative outcome. Conclusions: The present study explores a genomic setting for the treatment of AUD with naltrexone. According to our findings, the association between ADH1C*1 and ALDH2*2 variants and better outcomes suggests a successful treatment, whereas the ADH1B*3 mutated allele might lead to an unsuccessful treatment. Further studies should be performed to investigate the relationship between alcohol metabolizing genotypes, the family history of alcohol use disorders and the effect of naltrexone on the outcomes. Genotyping may be a valuable tool for precision-medicine and individualized approach, especially in the context of alcohol use disorders. The small number of subjects was the main limitation of the present study.
... Ethanol is metabolized into acetaldehyde in hepatocytes by cytochrome p450 2E1 (CYP2E1) and alcohol dehydrogenase (ADH). Acetaldehyde, with known direct mutagenic and tumorigenic effects in vivo and in vitro [64][65][66], is further metabolized by cytosolic Aldehyde dehydrogenase 1 (ALDH1) and mitochondrial aldehyde dehydrogenase 2 (ALDH2) to acetate [67]. In metabolism of ethanol, there is the production of NADH by ADH thereby leading to the alteration of Fig. (2). ...
Background:
Liver cancer is the fifth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Among the liver cancers, hepatocellular carcinoma has been reported to be responsible for 85-90% of primary liver cancer and it is the second most common cause of cancer mortality with 700,000 deaths documented annually. The major risk factors of HCC include chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) virus, chronic liver diseases, alcoholism as well as dietary carcinogens, such as aflatoxins. Highest incidence rates are estimated to occur in Asia and Africa.
Objective:
The effectiveness of current man-made agents in treating chronic liver disease is not satisfactory and they have uninvited side effects. Herbal medicines are extensively used all over the world; however, there is still a vast gap in their acceptance by the scientific community. Plants are rich in secondary metabolites and phytochemicals obtained from both, dietary and non-dietary sources. Natural plant products are potent therapeutic as well as chemopreventive agents for numerous chronic diseases like cardiovascular, metabolic, neurodegenerative and neoplastic diseases.
Results:
Dietary phytochemicals such as curcumin, resveratrol, quercetin, silibinin, N-trans-feruloyl octopamine, lycopene, emodin, caffeine, urolithin A and Phloretin have been found to be useful for the treatment of HCC and other diseases. According to recent reports 60% of the anticancer medication in current use has been obtained from natural sources.
Conclusion:
Thus, derivatives from plants have played an essential role in cancer prevention due to their pleiotropic abilities to scavenge free radicals, inhibit cell growth and induce apoptosis.
... CYP2E1 gene methylation and increased CYP2E1 mRNA are found in PD patient's brains [131]. These data suggest that epigenetic CYP2E1 alterations may facilitate the degenerative process through the metabolism of such xenobiotics and represent the genetic Rs6413419 G Alcohol dependence Alcohol [154] CYP2E1 * 1D Motor neuron disease [140] CYP2E1 RsaI Glioma [129] susceptibility to the disease [105]. These gene of CYP2E1 can influence the body's ability to interact with the detoxificant or the bioactivation of multiple chemical substrates. ...
Organisms have metabolic pathways that are responsible for removing toxic agents. We always associate the liver as the major organ responsible for detoxification of the body; however this process occurs in many tissues. In the same way, as in the liver, the brain expresses metabolic pathways associated with the elimination of xenobiotics. Besides the detoxifying role of CYP2E1 for compounds such as electrophilic agents, reactive oxygen species, free radical products, and the bioactivation of xenobiotics, CYP2E1 is also related in several diseases and pathophysiological conditions. In this review, we describe the presence of phase I monooxygenase CYP2E1 in regions of the brain. We also explore the conditions where protein, mRNA, and the activity of CYP2E1 are induced. Finally, we describe the relation of CYP2E1 in brain disorders, including the behavioral relations for alcohol consumption via CYP2E1 metabolism.
Outcomes related to disordered metabolism are common in alcohol dependence (AD). To investigate alterations in the regulation of body mass that occur in the context of AD, we performed a genome-wide association study (GWAS) of body mass index (BMI) in African Americans (AAs) and European Americans (EAs) with AD. Subjects were recruited for genetic studies of AD or drug dependence and evaluated using the Semi-structured Assessment for Drug Dependence and Alcoholism. We investigated a total of 2587 AAs and 2959 EAs with DSM-IV AD diagnosis. In the stage 1 sample (N = 4137), we observed three genome-wide significant (GWS) single-nucleotide polymorphism associations, rs200889048 (P = 8.98 * 10(-12) ) and rs12490016 (P = 1.44 * 10(-8) ) in EAs and rs1630623 (P = 5.14 * 10(-9) ) in AAs and EAs meta-analyzed. In the stage 2 sample (N = 1409), we replicated 278, 253 and 168 of the stage 1 suggestive loci (P < 5*10(-4) ) in AAs, EAs, and AAs and EAs meta-analyzed, respectively. A meta-analysis of stage 1 and stage 2 samples (N = 5546) identified two additional GWS signals: rs28562191 in EAs (P = 4.46 * 10(-8) ) and rs56950471 in AAs (P = 1.57 * 10(-9) ). Three of the GWS loci identified (rs200889048, rs12490016 and rs1630623) were not previously reported by GWAS of BMI in the general population, and two of them raise interesting hypotheses: rs12490016-a regulatory variant located within LINC00880, where there are other GWAS-identified variants associated with birth size, adiposity in newborns and bulimia symptoms, which also interact with social stress in relation to birth size; rs1630623-a regulatory variant related to ALDH1A1, a gene involved in alcohol metabolism and adipocyte plasticity. These loci offer molecular insights regarding the regulatory mechanisms of body mass in the context of AD.
Despite the profound clinical significance and strong heritability of alcohol use disorder (AUD), we do not yet have a comprehensive understanding of the naturally occurring genetic variance within the human genome that drives its development. This lack of understanding is likely to be due in part to the large phenotypic and genetic heterogeneities that underlie human AUD. As a complement to genetic studies in humans, many laboratories are using the invertebrate model organisms (iMOs) Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode worm) to identify genetic mechanisms that influence the effects of alcohol (ethanol) on behavior. While these extremely powerful models have identified many genes that influence the behavioral responses to alcohol, in most cases it has remained unclear whether results from behavioral-genetic studies in iMOs are directly applicable to understanding the genetic basis of human AUD.
In this review, we critically evaluate the utility of the fly and worm models for identifying genes that influence AUD in humans.
Based on results published through early 2015, studies in flies and worms have identified 91 and 50 genes, respectively, that influence 1 or more aspects of behavioral responses to alcohol. Collectively, these fly and worm genes correspond to 293 orthologous genes in humans. Intriguingly, 51 of these 293 human genes have been implicated in AUD by at least 1 study in human populations.
Our analyses strongly suggest that the Drosophila and C. elegans models have considerable utility for identifying orthologs of genes that influence human AUD.
Copyright © 2015 by the Research Society on Alcoholism.
