Genetic and Environmental Influences on Alcohol Metabolism in Humans (original) (raw)
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Alcoholism: Clinical and Experimental Research, 2006
Background: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. Methods: Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. Results: The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. Conclusions: Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.
Genetics of Alcohol Use in Humans: An Overview
… JOURNAL OF HUMAN …, 2008
Alcoholism is an extremely complex disease for which no generally accepted definition exists. There is a complex interaction between the socio-environmental context, the individual at risk, and the availability of alcohol. The result of family, twin and adoption studies suggest a significant genetic predisposition to the disease. Identifying novel genetic risk factors for common diseases is a global challenge in the post genomic era. Recent molecular genetic research into the causes of alcoholism has drawn attention to the potential role of alcohol and acetaldehyde metabolizing enzymes. Functional polymorphisms have been observed at various genes encoding these enzyme proteins that act as one of the biological determinants significantly influencing drinking behavior and the development of alcoholism and alcohol-induced organ damage. Most ethanol elimination occurs by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) systems via oxidation of ethanol to acetaldehyde and acetic acid. However, the legacy of alcoholism among certain ethnic groups suggests that genetic factors can increase an individual's vulnerability for this disease. An association study in patient cohorts and controls, from large populations involving whole genome scans, is the preferred approach for complex traits. To understand the molecular epidemiology and role of cofactors in alcoholism the standard phenotype-genotype correlation may be a useful tool. The present paper reviews various aspects of alcoholism including both the behavioural and molecular etiologies.
Alcoholism: Clinical and Experimental Research, 1999
Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.
Alcohol Dehydrogenase Polymorphisms Influence Alcohol-Elimination Rates in a Male Jewish Population
Alcoholism: Clinical & Experimental Research, 2004
Background: Genetic variation in the alcohol dehydrogenase (ADH) enzyme is associated with an aversion to alcohol and a lower risk of alcoholism among Asians. There is growing evidence of a functional role of the ADH2*2 allele in alcohol-drinking patterns among Jews, who have traditionally exhibited low rates of alcoholism and alcohol-related problems. The mechanism by which this allelic effect is mediated is not yet clearly understood. This study examined the effect of ADH2*2 on alcohol-elimination rates (AER) under experimental conditions. Methods: Young adult male Jews (N ϭ 109) received an intravenous alcohol infusion; metabolism was measured by using standard breath alcohol concentration tests. A clamping technique was used to achieve and maintain a target breath alcohol concentration of 50 mg/100 ml for a defined time period. The AER at steady state was calculated. The alcohol disappearance rate was also calculated from the descending limb slope. Polymerase chain reaction was used for allelic determination of the ADH2 and ADH3 loci.
Genetic and Environmental Influences on Ethanol Consumption: Perspectives From Preclinical Research
Alcoholism: Clinical and Experimental Research, 2010
Alcohol use disorders (abuse and dependence, AUD) are multifactorial phenomena, depending on the interplay of environmental and genetic variables. This review describes current developments in animal research that may help (a) develop gene therapies for the treatment of alcoholism, (b) understand the permissive role of stress on ethanol intake and (c) elucidate why exposure to ethanol early in life is associated with a greater risk of AUD. The polymorphisms found in liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) affect the elimination of ethanol and the susceptibility to ethanol intake. A highly-active ADH protects against alcoholism, an effect related to a pre-steady state burst in arterial acetaldehyde. Social stressors, such as repeated early maternal separation or social defeat, exert a permissive effect on ethanol intake, perhaps by altering the normal development of the hypothalamic-pituitary-adrenal axis. Ethanol exposure during gestation, infancy or adolescence increases the likelihood of AUD later in life. Early perception of ethanol's positive and negative (anti-anxiety) reinforcing effects may play a role in this phenomenon. The review underscores the advantages of using pre-clinical animal models of AUD and highlights points of intersection between the topics to help design a more integrated approach for the study of alcohol-related problems.
Hypertension Research, 2009
Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop hypertension. In addition, some polymorphisms of the alcohol metabolism genes have been reported to exert significant impacts on the risk of alcoholism. We investigate the relevance of genetic susceptibility to drinking behavior and its influence on the sensitivity to pressor effects of alcohol in the Japanese general population. We initially screened SNPs in four candidate genes by resequencing. From 35 SNPs thus identified, 10 tag SNPs were selected and used for large-scale association analysis in a total of 5724 subjects. Among the SNPs tested, significant association (Po0.001) with drinking behavior was observed for ADH1B Arg47His (rs1229984) and ALDH2 Glu487Lys (rs671) polymorphisms. All subjects with Lys homozygote (AA genotype) of rs671 turned out to be nondrinkers and the combination of two SNP genotypes appeared to substantially influence people's drinking behavior in a synergistic manner. rs671 was significantly associated with blood pressure (P¼0.0001-0.0491) in subgroups of drinkers. In the context of gene-environment interaction, our data clearly show the genetic impacts of two SNPs on drinking behavior and of one SNP on the sensitivity to the pressor effects of alcohol in the Japanese general population.
Commentary: Perspectives on alcohol-related gene and environment interplay in diverse populations
The American journal on addictions, 2017
Racial/ethnic groups comprise more than 20% of the U.S. population, but many experience disproportionately high risk for alcohol misuse, often resulting in higher rates of alcohol-associated consequences. Completion of mapping the human genome has launched rapidly evolving research methods aimed at improved understanding of genetic contribution to disease. Despite decades of research on the influence of genetic and environmental risks on alcohol use disorders and outcomes, few studies have included racial/ethnic subpopulations in sufficient numbers to allow for proper statistical analysis. The papers in this special issue help to elucidate current knowledge on the etiology of genetic and environmental contributors and potential moderators of alcohol use and associated problems among racial/ethnic populations. The lack of racial/ethnic diversity across many genetic studies contributes to challenges in interpretation of findings and eventually applications to precision medicine. Propo...
Alcoholism: Clinical and Experimental Research, 2006
Background: Risk and protective factors for alcohol use disorders (AUDs) are complex and reflect both environmental and genetic factors. Genetic components account for about 50% of the variation and influence several phenotypes, including the level of response (LR) to alcohol as well as alcohol-metabolizing enzyme polymorphisms. Variations in the ADH1B and ADH1C genes may influence the LR to alcohol by increasing levels of acetaldehyde during alcohol metabolism, although most data on this question come from Asian populations.