Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis (original) (raw)
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Alcoholism: Clinical and Experimental Research, 2001
Background: Two of the class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode for multiple isozymes that differ in their kinetic properties. Polymorphisms at both of these gene loci have been linked to alcoholism and/or alcohol-induced disabilities in some populations. At the ADH2 locus, three polymorphisms are present (ADH2*1, ADH2*2, ADH2*3). ADH2*3 allele codes for a high K m and V max variant that has been reported to occur exclusively in African Americans and some tribes of Native Americans. In African Americans, the presence of the ADH2*3 allele is associated with protection from alcohol-related birth defects. However, its relationship to risk for alcoholism in African Americans remains relatively unexplored. Methods: The participants were 97 African American young adults (18-25 years old). A structured interview was used to gather information on demographics, psychiatric diagnoses, personal drinking and drug use history, and familial history of alcohol use disorders. A blood sample was obtained from each participant and leukocyte DNA extracted and genotyped for the presence of ADH2*3 alleles. The specific aim of the study was to investigate the associations between the presence of the ADH2* 3 allele and personal and family history of alcohol use/abuse. Results: Thirty participants (31%) had at least one ADH2*3 allele and two were homozygous for the allele. A significant association between the presence of an ADH2*3 allele and a negative family history of alcoholism was uncovered (p Ͻ 0.04). No significant associations of an ADH2*3 allele with personal history of alcohol use disorders or with current drinking were found; however, power to detect associations was limited in this population because half the population did not drink regularly. Conclusions: Because family history of alcoholism is one of the best predictors of the development of alcohol use disorders, this pilot study suggests that, in this sample of African American young adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism.
Alcoholism-clinical and Experimental Research, 2008
The genes coding for ethanol metabolism enzymes [alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] have been widely studied for their influence on the risk to develop alcohol dependence (AD). However, the relation between polymorphisms of these metabolism genes and AD in Caucasian subjects has not been clearly established. The present study examined evidence for the association of alcohol metabolism genes with AD in the Irish Affected Sib Pair Study of alcohol dependence.
Alcoholism: Clinical and Experimental Research, 2011
Background-Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. Methods-The present study tested for associations between alcohol dependence and related traits and 22 single nucleotide polymorphisms (SNPs) spanning the seven ADH genes. Participants included 586 adult men and women recruited from eight contiguous Native American reservations. A structured interview was used to assess DSM-III-R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. Results-No evidence for association with the alcohol dependence diagnosis was observed, but a SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and a SNP at the 5' end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms (p=0.0018 and 0.0012, respectively). Further, a haplotype analysis of these two SNPs suggested haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype (p=0.000006). Conclusions-These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence.
Human Genetics, 2003
Enzymes encoded by two gene families, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B(previously ADH2), ADH1C (pre-viously ADH3), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe (n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study.
A Preliminary Data: Distribution of ADH1C Genotypes and Alleles in Turkish Alcoholic Subjects
group (23%) compared to that of the alcohol-dependents (42%, p ! 0.0001). We obtained no statistically significant difference among the ADH1C genotype groups regarding age. Conclusions: These findings suggest that a significantly higher presence of ADH1C * 2 allele is associated with alcohol dependence in a Turkish population. Studies with other related polymorphisms are needed to more precisely estimate the association of alcohol dependence with ADH1C .
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.
Linkage Disequilibrium at the ADH2 and ADH3 Loci and Risk of Alcoholism
The American Journal of Human Genetics, 1999
Two of the three class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode known functional variants that act on alcohol with different efficiencies. Variants at both these genes have been implicated in alcoholism in some populations because allele frequencies differ between alcoholics and controls. Specifically, controls have higher frequencies of the variants with higher V max (ADH2*2 and ADH3*1). In samples both of alcoholics and of controls from three Taiwanese populations (Chinese, Ami, and Atayal) we found significant pairwise disequilibrium for all comparisons of the two functional polymorphisms and a third, presumably neutral, intronic polymorphism in ADH2. The class I ADH genes all lie within 80 kb on chromosome 4; thus, variants are not inherited independently, and haplotypes must be analyzed when evaluating the risk of alcoholism. In the Taiwanese Chinese we found that, only among those chromosomes containing the ADH3*1 variant (high V max ), the proportions of chromosomes with ADH2*1 (low V max ) and those with ADH2*2 (high V max ) are significantly different between alcoholics and controls ( ). The proportions of chromosomes with Ϫ5 P ! 10 ADH3*1 and those with ADH3*2 are not significantly different between alcoholics and controls, on a constant ADH2 background (with ADH2*1, ; with P ϭ .83 ADH2*2, ). Thus, the observed differences in the P ϭ .53 frequency of the functional polymorphism at ADH3, between alcoholics and controls, can be accounted for by the disequilibrium with ADH2 in this population.