Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population

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 = 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. RESULTS: The mean AER among ADH2*2 carriers was significantly higher (8.09 +/- 1.4 g/hr) than among ADH2*1 homozygotes (7.14 +/- 1.5 g/hr; p = 0.003). Significance was retained on adjustment for potential confounding covariates. The ADH2 allele explains 8.5% of the AER variance in this population. Little AER difference was observed across ADH3 genotype groups. The slope of the descending limb increased with increasing copies of the ADH2*2 allele. CONCLUSIONS: The rate of alcohol elimination is significantly associated with the ADH2 genotype of Jewish males. Evidence for variation in alcohol metabolism across ADH genotypic groups provides support for the role of physiologic protective factors in alcohol drinking and suggests that reduced drinking among Jews may be genetically as well as environmentally determined. We believe that application of the novel "Indiana clamp" enhances AER measurement accuracy, allowing for detection of hitherto undetectable differences.     

Alcohol dependence symptoms and alcohol dehydrogenase 2 polymorphism: Israeli Ashkenazis,Sephardics, and recent Russian immigrants

BACKGROUND: Jews have lower rates of alcohol-related problems than other Caucasians. The ADH2*2 allele of the alcohol dehydrogenase 2 (ADH2 ) gene protects against alcoholism in Asians and is found in approximately 20% of Jews. We studied the relationship of ADH2*2 to DSM-IV dependence severity in a random community sample of Israeli Ashkenazis, recent Russian immigrants (also Ashkenazis), and Sephardics. METHODS: Subjects participated in a structured interview that included highly reliable questions on DSM-IV alcohol dependence symptoms. ADH2 genotype was determined for 68 subjects. RESULTS: Recent Russian immigrants had more past and lifetime DSM-IV dependence symptoms. Sephardics had a higher prevalence of ADH2*2 than Ashkenazis. Controlling for group and other potentially confounding factors, ADH2*2 was associated with a lower lifetime DSM-IV alcohol dependence severity, although this differed somewhat within groups. CONCLUSIONS: ADH2*2 protects against dependence severity in Jewish samples. Future work in larger samples should address genetic and environmental factors that affect the relationship of ADH2*2 to alcohol consumption and dependence.     

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals

OBJECTIVE: To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. MATERIAL AND METHODS: We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. RESULTS: In the population examined the ADH2*1 allele frequency was 97.97%.The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2 /*2 genotype. CONCLUSIONS: In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.     

ALDH2 and ADH1B interactions in retrospective reports of low-dose reactions and initial sensitivity to alcohol in Asian American college students

Background: A mechanistic model has been proposed for how alcohol‐metabolizing gene variants protect individuals from the development of alcohol use disorders, with heightened sensitivity to alcohol being an early step (endophenotype) in this model. This study was designed to determine whether possession of 2 alcohol‐metabolizing genes variations, the aldehyde dehydrogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self‐reported sensitivity to alcohol at low doses and at initial use. Methods: Asian–American college students (N = 784) of Chinese and Korean descent were genotyped at the ALDH2 and ADH1B loci and assessed for lifetime alcohol symptoms following 1 or 2 drinks and level of response to alcohol during the first 5 lifetime drinking episodes. Results: Participants who had an ALDH2*2 allele were more likely to report experiencing all 6 low‐dose symptoms and having heightened initial response to alcohol. An interaction was found between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self‐reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele. Conclusions: These findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol‐related problems.     

Association of the ADHIB*3 allele with alcohol-related phenotypes in Trinidad

BACKGROUND: Two of the class I alcohol dehydrogenase (ADH) genes located on chromosome 4 (ADH1B and ADH1C) encode for multiple isozymes that differ in their kinetic properties. At the ADH1B locus, 3 polymorphisms are present (ADH1B(*)1, ADH1B(*)2, ADH1B(*)3). ADH1B(*)2 (found mostly in individuals of East Asian and Jewish descent) and ADH1B(*)3 (found mostly in individuals of African decent) alleles encode for a more active enzyme variants than ADH1B(*)1 and the presence of these alleles has been associated with protection from alcohol dependence. The relationship between these alleles and alcohol-associated phenotypes has not been previously investigated in individuals living in the Caribbean. METHODS: One hundred thirty-three alcohol-dependent individuals of either East Indian or African ancestry and 98 controls matched by age, sex, education, and ethnicity participated in the study. A structured interview [the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)] was used to gather information on demographics, psychiatric diagnoses, personal drinking, and drug use history. Leukocyte DNA extracted from a blood sample obtained from each participant was genotyped at the ADH1B locus. Serum levels of the liver enzymes alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) as well as the presence of HIV, hepatitis B surface antigen, and antihepatitis C virus antibody were also assayed. The specific aim of the study was to investigate the associations between ADH1B alleles and alcohol dependence, drinking history, and liver function in individuals from the 2 major ethnic groups of Trinidad (individuals of African and East Indian ancestry). RESULTS: Twenty-eight of the Afro-Trinidadian (Afro-TT) participants (41%) and 1 Indo-Trinidadian (Indo-TT) (>1%) had at least 1 ADH1B(*)3 allele and 3 Afro-TT were homozygous for the allele. African participants with at least 1 ADH1B(*)3 allele were found to be significantly less likely to be alcohol dependent (p<0.018), and to have lower alcohol consumption levels (p<0.05). Among those participants who were alcohol dependent, ADH1B(*)3 was associated with significantly higher levels of ALT (p<0.05). CONCLUSIONS: This study suggests, in this sample of Trinidadians, that the ADH1B(*)3 allele is associated with protection from the development of alcoholism but is also associated with enhanced risk for elevated serum ALT levels in those individuals who do become alcohol dependent.     

Association of the ADH2*3 Allele With A Negative Family History Of Alcoholism in African American Young Adults

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 Km and Vmax 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 < 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.     

Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China

AIM＂ TO evaluate the impact of alcohol dehydrogenase 2 （ADH2） and aldehyde dehydrogenase 2 （ALDH2） polymorphisms on esophageal cancer risk. METHODS;One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2 genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer （PCR-CTPP） method. Unconditional logistic regression was used to calculate the odds ratios （OR） and 95% confidence interval （95% CI）. RESULTS; Both ADH2＊1 allele and ALDH2＊1/＊2 allele showed an increased risk of developing esophageal cancer. The adjusted OR （95% CI） for ADH2＊1 allele compared with ADH2＊2/＊2 was 1.65 （95% CI = 1.02-2.68） and 1.67 （95% CI = 1.02-2.72） for ALDH2＊1/＊2 compared with ALDH2＊1/＊1. A significant interaction between ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83 （95% CI = 1.13-2.95）. Furthermore, when compared with ADH2＊2/＊2 and ALDH2＊1/＊1 carriers, ADH2＊1 and ALDH2＊2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers     

Associations of variations in alcohol dehydrogenase genes with the level of response to alcohol in non-Asians

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. METHODS: This study evaluated associations of ADH1B and ADH1C genotypes in a non-Asian sample. Participants (N = 117, 69.2% female) were 18- to 29-year-old men and women, primarily Caucasian (70.1%) and black (26.5%), recruited in San Diego, California. The Semi-Structured Assessment for the Genetics of Alcoholism Interview was used to assess demographic, substance use, and psychiatric history information, and the Family History Assessment Module was used to determine first-degree family history of alcohol dependence. An alcohol challenge paradigm was used to gather data on the LR to alcohol over 210 minutes. RESULTS: Participants with the ADH1B*1/*2 genotype had a higher LR to alcohol early in the alcohol challenge (i.e., 30, 60, and 90 minutes after drinking) as measured by both alcohol-related changes in subjective feelings of intoxication and body sway, even when controlling for sex and Russian/Eastern European ancestry. A similar trend was seen for ADH1C*1/*1 genotype, although the results were not significant. CONCLUSIONS: These findings suggest that studies searching for genes relating to the LR to alcohol as a vulnerability factor for AUDs should consider controlling for ADH1B genotype, as the ADH1B*2 allele could obscure the impact of other genetic polymorphisms.     

Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence

BACKGROUND: The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism. We hypothesized that the ADH1B and ALDH2 genes might interact with the DRD2 gene and that the association between the DRD2 gene and alcohol dependence might be affected by different ADH1B and ALDH2 genotypes. This study examined whether the DRD2 gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between the DRD2 gene and alcohol-metabolizing genes in a specific subtype of alcohol dependence. METHODS: Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety-depression (ANX/DEP ALC), and 129 with anxiety-depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and Schizophrenia-Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM-IV criteria. RESULTS: The DRD2 gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the control of the ALDH2*1/*1 and ADH1B*1/*2 genotypes. CONCLUSIONS: ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with the DRD2 gene only under the stratification of ADH1B*1/*2 or ALDH2*1/*1, the DRD2 gene might interact with the ADH1B gene and the ALDH2 gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population.     

Alcohol-metabolizing enzyme gene polymorphisms and alcohol chronic pancreatitis among Polish individuals

Background and aims. Chronic pancreatitis develops in 5–10% of alcohol addicts. In developed societies, alcohol is the cause of chronic pancreatitis in at least 70–80% of cases. The genetic polymorphism of enzymes involved in alcohol metabolism is relevant in the etiopathogenesis of chronic pancreatitis. The aim of the study was to find the ADH, ALDH2 and CYP2E1 alleles and genotypes in the Polish population that are likely to be responsible for higher susceptibility to chronic alcohol pancreatitis. Material and methods. We determined the allele and genotype of ADH2, ADH3, ALDH2 and CYP2E1 in 141 subjects: 44 with alcohol chronic pancreatitis (ACP), 43 healthy alcoholics and 54 healthy non-drinkers as the controls. Genotyping was performed using PCR-RELP methods on white cell DNA. Results. ADH2*1, ADH3*1 alleles and ADH2*1/*1, ADH3*1/*1 genotypes were statistically more frequent among the patients with ACP than among the controls. The ADH3*2/*2 genotype was more frequent among “healthy alcoholics” and in the controls than among those with ACP. In the studied group, only the ALDH2*1 allele was detected, all patients were ALDH2*1/*1 homozygotic. Differences in the CYP2E1 allele and genotype distribution in the examined groups were not significant. Conclusion. In the Polish population examined, ADH3*1 and ADH2*1 alleles may be risk factors for the development of alcoholism. The ADH3*2/*2 genotype may confer protection against ACP. CYP2E1 gene polymorphism is not related to alcoholism and ACP. The Polish population examined is ALDH2*1/*1 homozygotic.     

Low Frequency of the ADH2*2 Allele among Atayal Natives of Taiwan with Alcohol Use Disorders

Genetic variation at two polymorphic alcohol dehydrogenase loci, ADH2 and ADH3, and at the polymorphic mitochondrial aldehyde dehydrogenase locus, ALDH2, may influence the risk of developing alcoholism by modulating the rate of elimination of ethanol and the rate of formation and elimination of acetaldehyde. Populations differ in allele frequencies at these loci. We determined the genotypes at all three of these loci in Atayal natives of Taiwan. The frequencies of ADH2'2, ADH3'1, and ALDH2'1 alleles (0.91, 0.99, and 0.95, respectively) were significantly higher among the Atayal than among a predominantly Han Chinese population from Taiwan. Among the Atayal, the group with alcohol use disorders (alcohol dependence and alcohol abuse) had a significantly lower frequency of the ADH2'2 allele (0.82) than those without alcohol use disorders (0.91). The ADH2*2 allele encodes the β2 subunit; isozymes containing β₂ sub-units oxidize alcohol faster in vitro than the β₁β₁ isozyme encoded by ADH2*1. Thus, the simplest explanation for these data is that individuals with a β2 isozymes have a higher rate of ethanol oxidation, which is a deterrent to alcohol abuse and dependence in some individuals. The Atayal with alcohol use disorders also had a lower frequency of ALDH2*2 than the controls; this allele is known to be responsible for the alcohol-flush reaction among Asians, and thereby deters drinking.     

ADH and ALDH Polymorphisms and Alcohol Dependence in Mexican and Native Americans

Background: Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. Objectives and methods: Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county. Results: Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. Conclusions and Scientific Significance: Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations.     

Prenatal Alcohol Exposure and Interhemispheric Transfer of Tactile Information: Detroit and Cape Town Findings

Background:  Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults.
Methods:  In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation.
Results:  In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (≥5 standard drinks) during pregnancy than if she drank regularly (M ≥ 1 drink/day) without binge drinking.
Conclusions:  These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.     

Alcohol and Aldehyde Dehydrogenase Genotypes and Drinking Behavior in Japanese

The effects of the genotype of alcohol dehydrogenase-2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.     

An fMRI Study of Number Processing in Children With Fetal Alcohol Syndrome

Background: Number processing deficits are frequently seen in children exposed to alcohol in utero. Methods: Functional magnetic resonance imaging was used to examine the neural correlates of number processing in 15 right‐handed, 8‐ to 12‐year‐old children diagnosed with fetal alcohol syndrome (FAS) or partial FAS (PFAS) and 18 right‐handed, age‐ and gender‐matched controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, using Proximity Judgment and Exact Addition tasks. Results: Control children activated the expected fronto‐parietal network during both tasks, including the anterior horizontal intraparietal sulcus (HIPS), left posterior HIPS, left precentral sulcus, and posterior medial frontal cortex. By contrast, on the Proximity Judgment task, the exposed children recruited additional parietal pathways involving the right and left angular gyrus and posterior cingulate/precuneus, which may entail verbally mediated recitation of numbers and/or subtraction to assess relative numerical distances. During Exact Addition, the exposed children exhibited more diffuse and widespread activations, including the cerebellar vermis and cortex, which have been found to be activated in adults engaged in particularly challenging number processing problems. Conclusions: The data suggest that, whereas control children rely primarily on the fronto‐parietal network identified in previous studies to mediate number processing, children with FAS/PFAS recruit a broader range of brain regions to perform these relatively simple number processing tasks. Our results are consistent with structural neuroimaging findings indicating that the parietal lobe is relatively more affected by prenatal alcohol exposure and provide the first evidence for brain activation abnormalities during number processing in children with FAS/PFAS, effects that persist even after controlling statistically for group differences in total intracranial volume and IQ.     

Alcohol-metabolizing enzyme gene polymorphisms in the Basque Country, Morocco, and Ecuador

Background: Genes ADH1B and ADH1C have certain functional SNPs that are related to alcoholism. The frequencies of these polymorphisms vary between populations, so studying them in populations made up of groups with different phylogeographic origins requires an individualized analysis of each group. In the Basque Country, various recently arrived foreign groups live side by side with the original Southern European population, particularly North Africans from Morocco and Hispanics from Ecuador. This study sets out to examine the distribution of the frequencies of alleles that encode alcohol dehydrogenase with different metabolization rates, as higher rates make for greater susceptibility to alcoholism. Methods: Four SNPs: rs1229984, rs2066702, rs698, and rs1693482 using Taqman technology with a Rt‐PCR were studied in a sample of 114 European individuals originating from the Basque Country, 100 North Africans from Morocco, and 109 Hispanics from Ecuador. The allele and genotype frequencies were calculated using Genepop v4.0. The most frequent haplotypes were estimated using the ELB algorithm with Arlequin v3.01. A breakdown of the complete disequilibrium commonly observed between the 2 missense polymorphisms that distinguish the common ADH1C alleles rs698 and rs1693482 was observed and confirmed by sequencing in 2 individuals from the Basque Country. Results: A higher frequency of protective allele ADH1C*1 was found in the North African population group. Haplotype combinations are also studied, and the rare association of alleles ADH1B*2–ADH1C*2 was observed in the Southern European group in the Basque Country, along with an allele not hitherto described in the ADH1C locus. Conclusions: This study provides the first data published on the allele and genotype frequencies of the ADH1C locus in the Moroccan population and on the ADH1B and ADH1C loci in the Ecuadorian population. The study shows differences in the distribution of the frequency of allele ADH1C*1 between the Basque Country and Moroccan populations, and a new allele not described to date.     

Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan

BACKGROUND: suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism. Recent studies have suggested that either physiological tolerance of blood acetaldehyde, or innate insensitivity to it, or both may play a crucial role in keeping alcoholism from developing by protecting against adverse reactions. ALDH inactive form resulting from ALDH2*2, which slows the elimination of acetaldehyde and the more active isozymes produced by ADH1B*2, could generate higher acetaldehyde levels and thus deter heavy drinking (). The genotype frequency of ADH1B*2/*2 and ALDH2*(1/*2 or 2/*2), which are regarded protective against drinking behavior, is about 70% and 50%, respectively, among the Han Chinese population in Taiwan (Chen et al., 1999a). Most previous studies, however, have failed to separate the effects of antisocial personality disorder from those of alcoholism because of their high comorbidity. To understand the relationship among alcoholism, antisocial personality disorder, and the protective effects of ADH and ALDH, it is necessary to recruit individuals with antisocial personality disorder but without alcoholism. This study was designed to stratify subjects by various ADH1B and ALDH2 genotypes for a more effective association study. The strata were: antisocial alcoholics, antisocial non-alcoholics, community alcoholics, and normal controls. METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder. RESULTS: We found no difference of ADH1B*2 allele frequency between the subjects of antisocial alcoholism and subjects of antisocial non-alcoholism, but we found significant difference of ALDH2*2 allele between these two groups. CONCLUSIONS: We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.     

Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption, and risk of breast cancer

BACKGROUND: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. METHODS: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. RESULTS: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C*1 or ADH1B*2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A>G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls. CONCLUSIONS: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A>G needs further evaluation.