Meta-analysis of the effects of alcohol dehydrogenase genotype on alcohol dependence and alcoholic liver disease

The purpose of this paper is to assemble and evaluate existing data on the effect of genetic variation in ADH2 and ADH3 on the risk of alcohol dependence, and on the risk of alcoholic liver disease. Calculations of odds ratios and their confidence limits, and tests for heterogeneity of the results from the available studies, have been performed. It is clear that possession of the ADH2-2 allele decreases the risk of alcohol dependence, but it increases the risk of alcoholic liver disease among alcoholics. ADH3 variation also has significant effects on alcohol dependence, which may be due to linkage to ADH2; the ADH3 effect differs significantly between Asian and European subjects. Therefore ADH genotype has substantial effects on risk of alcohol dependence and alcoholic liver disease, but more work is needed on the generalizability of these findings to non-Asian populations, and on possible mechanisms.     

ALDH2, ADH1B and alcohol expectancies: Integrating genetic and learning perspectives.

The present study evaluated associations of ALDH2 and ADH1B genotypes with alcohol expectancies and drinking behavior in a sample of Asian American young adults. In addition to assessing global alcohol expectancies, the authors developed a measure of physiological expectancies to evaluate an expectancy phenotype specific to the mechanism by which ALDH2 and ADH1B variations presumably influence drinking behavior. Compared with individuals with the ALDH2*1/*1 genotype, those with the ALDH2*2 allele reported greater negative alcohol expectancies, greater expectancies for physiological effects of alcohol and lower rates of alcohol use. ADH1B was not associated with alcohol expectancies or drinking behavior. Hierarchical models showed that demographic factors, ALDH2 genotype, and expectancy variables explained unique variance in drinking outcomes. Mediation tests showed significant indirect effects of ALDH2 on drinking frequency and peak lifetime consumption through expectancies. These results provide support for influences of genetic factors and alcohol sensitivity on alcohol-related learning and suggest the importance of developing biopsychosocial models of drinking behavior in Asian Americans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Racial variation of factor VII activity and antigen levels and their correlates in healthy Chinese and Indians at low and high risk for coronary artery disease

We examined the genotypes of ALDH2, ADH2, ADH3 and P-4502E1 loci of alcoholics and nonalcoholics. Also we compared the frequencies of the homozygous ALDH2*1/1 genotype and heterozygous ALDH2*1/2 genotypes in alcoholics. Our study reported differences in the allelic frequencies of ALDH2, ADH2 and ADH3 loci between alcoholics and nonalcoholics. For alcoholics, it was indicated that ADH2 and ADH3 plays an important role for alcoholism. For genotypes of P-4502E1, no significant difference was observed between alcoholics and nonalcoholics. Alcoholics with the heterozygous ALDH2*1/2 genotype had significantly higher frequency of the ADH2*1 than that of alcoholics with ALDH2*1/1 genotype. Concerning the alcoholics with the heterozygous ALDH2*1/2 genotype, we assumed that ADH2*1 plays a role for the development of alcoholism.     

Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians.

Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant *2 allele was protective against alcohol dependence, and possession of a 2nd *2 allele did not offer significant additional protection. The protective effects of these 2 gene polymorphisms were independent. Diagnostic criteria, recruitment strategy, and Japanese ethnicity moderated the effect of ALDH2*2. Recruitment strategy and gender moderated the effect of ADH1B*2. These findings highlight the importance of methodological issues and potential gene-gene and gene-environment interactions that must be considered when examining relationships between genetic polymorphisms and phenotypes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

ALDH2 Status and Conduct Disorder Mediate the Relationship Between Ethnicity and Alcohol Dependence in Chinese, Korean, and White American College Students.

This study examined aldehyde dehydrogense (ALDH2) gene status, alcohol dehydrogense (ADH2) gene status, conduct disorder, and alcohol dependence in Chinese, Korean, and White American college students. Chinese had a lower rate of alcohol dependence (5%) than Koreans (13%) and Whites (17%). Koreans had a higher rate of conduct disorder (15%) than Whites (9%) and Chinese (6%). The relationship of ethnicity to alcohol dependence was mediated by ALDH2 status and conduct disorder, although Chinese ethnicity remained significant. ADH2 status was not related to alcohol dependence with ALDH2 included, and no interactions were significant. Results suggest that different rates of risk (e.g., conduct disorder) and protective (e.g., ALDH2 status) factors partially account for ethnic differences in rates of alcohol dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genotypes of alcohol dehydrogenase and aldehyde dehydrogenase and their significance for alcohol sensitivity

Genotypes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) loci were determined, using allele specific oligonucleotides. Gene frequencies of ADH2(1) and ADH2(2) were 0.29 and 0.71, respectively, in the Japanese control group. No significant difference was found in the ADH2 genotype between the patients and the control group. Gene frequency of ALDH2(1) and ALDH2(2) were 0.65 and 0.35 in the control group, while 0.93 and 0.07, respectively in the patient group. Most of the patients, 20 out of 23, were homozygous Caucasian type. All individuals with homozygous atypical ALDH2(2)/ALDH2(2) and most of those with heterozygous atypical ALDH2(1)/ALDH2(1) were alcohol flushers, while all of the usual ALDH2(1)/ALDH2(1) were nonflushers. The results indicate that Japanese with the atypical ALDH2(2) allele are at a much lower risk in developing alcoholic liver disease than those with usual ALDH2(1)/ALDH2(1), presumably due to their sensitivity to alcohol intoxication.     

Development of a questionnaire method to discriminate between typical and atypical genotypes of low Km aldehyde dehydrogenase in a Japanese population

Nearly half of all Orientals exhibit aversive symptoms, such as "Oriental flushing" or palpitation, during alcohol consumption. This high alcohol sensitivity among Orientals has been attributed to a highly prevalent polymorphism in low Km aldehyde dehydrogenase (ALDH2). In the present study, we attempted to develop a reliable questionnaire method to probe the frequency of alcohol drinking-related symptoms to estimate the ALDH2 genotype. Four-hundred twenty-four male and 100 female workers provided blood samples for polymerase chain reaction analysis and completed the questionnaire. We performed a stepwise logistic regression analysis to discriminate between the typical homozygote (ALDH2*1/*1) and the atypical heterozygote (ALDH2*1/*2) in male subjects. Because of the limitation in the sample size for ALDH2*2/*2, this genotype was not included in the analysis. Results revealed that only three symptoms (facial flushing, flushing elsewhere, and palpitation) were enough to correctly predict the ALDH2 genotypes in approximately 89% of all subjects. The present questionnaire method (ALcohol Sensitivity screening Test; ALST) takes a little time and effort for the genotype determination, and may be especially useful in epidemiological studies with a large sample size or with subjects from whom DNA samples are not available.     

The interaction between alcohol consumption and GSTM1 genotype on polycyclic aromatic hydrocarbon-DNA adduct levels in breast tissue

We investigated the association between alcohol consumption, GSTM1 genotype, and polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels in breast tissue. Women referred for breast surgery were enrolled prior to surgery, responded to an interview, and gave a blood sample. Women diagnosed with ductal carcinoma in situ and invasive ductal or lobular cancer were defined as cases, and women with benign conditions without atypia were defined as controls. Paraffin-embedded tumor and nontumor tissue from cases and benign tissue from controls were retrieved from the pathology samples. GSTM1 genotype status was determined by PCR using WBC DNA, and PAH-DNA adduct levels were measured in breast tissue using immunohistochemistry. In tumor and nontumor tissue from cases, the GSTM1-null genotype was associated with increased adduct levels among current alcohol consumers but not among nondrinkers. In nontumor tissue, the interaction between genotype and alcohol consumption was significant (P=0.02), but in tumor tissue, the interaction did not achieve statistical significance (P=0.10). In benign tissue from controls, there was no association between genotype and adducts, regardless of drinking status. Among subjects with the null genotype who drank alcohol, adduct levels were significantly higher in tumor and nontumor tissue from cases than in benign tissue from controls. These results indicate the presence of a novel gene-lifestyle interaction that influences PAH-DNA adduct levels in breast tissue from cases but not controls. This apparent difference in PAH metabolism in response to alcohol may be an important clue as to how alcohol influences breast cancer risk.     

Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependence

BACKGROUND: Posttraumatic stress disorder (PTSD) often co-occurs with alcohol dependence, yet little is known about treatment of this comorbidity. The serotonin selective reuptake inhibitors have been shown preliminarily to be effective in decreasing symptoms of PTSD but have not been studied in individuals with comorbid alcohol dependence. This is of particular interest as the SSRIs also have a modest effect in decreasing alcohol consumption. METHOD: In this preliminary trial, nine subjects with comorbid PTSD and alcohol dependence were treated in an open-label trial with sertraline for a 12-week period. Symptoms of PTSD and depression were monitored monthly with the Impact of Event Scale and the Hamilton Rating Scale for Depression (HAM-D). Alcohol consumption was monitored by a self-report instrument (Time-Line Follow-Back). RESULTS: There were significant decreases in all three symptom clusters of PTSD measured by overall PTSD symptom scores (p < or = .001) and in HAM-D scores (p < or = .001) during the follow-up period. Days of abstinence increased and average number of drinks decreased during the follow-up period. Four subjects claimed total abstinence during the follow-up period. CONCLUSION: While limited by small sample size and the open-label, nonblinded study design, this study suggests that sertraline may be useful in the treatment of PTSD complicated by alcoholism. The medication was well tolerated and subjects showed improvement in PTSD symptoms as well as decreased alcohol consumption. A controlled trial of sertraline in this population would be of interest.     

The effects of neurotransmitter antagonists and glucose on luteinizing hormone secretion in growth-restricted wethers

Previous studies have reported some significant participation by gastric alcohol dehydrogenase (ADH) in alcohol metabolism, similar to that by hepatic ADH. However, the localization of this ADH in the stomach is not yet determined and there has been no study on the localization of ADH in the stomach of alcoholics before and after abstinence from alcohol. The aim of the present study was to reveal any changes between before and after abstinence from alcohol in the immunohistochemical localization of ADH using biopsy specimens from the gastric mucosa. Twenty male alcoholics (aged 47.8 +/- 7.4 yrs) gave signed informed consent for this investigation. Esophago-gastro-duodenoscopy (EGD) and gastric corpus biopsy were performed just before abstinence and at one month later. ADH in the biopsy specimens was immunohistochemically examined with an anti-ADH antibody, using confocal laser scanning microscopy. The fluorescence intensity for ADH was compared for each pair of specimens before and after abstinence from alcohol using an image analyzer. Age, total alcohol consumption, degree of gastritis, and the liver function tests of all patients were also analyzed. The strongly immuno-positive cells for ADH in the gastric mucosa were identified as parietal cells. The fluorescence intensity for ADH was significantly higher in those specimens obtained after abstinence than in those before abstinence (p < 0.005). The immunoreactibility for ADH in the cells assessed by confocal laser scanning microscopy was greatly improved after abstinence of alcohol, suggesting recovered alcohol metabolism in the gastric mucosa after abstinence from alcohol. The present study, demonstrating the cellular ADH localization in the gastric mucosa before and after abstinence from alcohol, may contribute to clarifying gastric alcohol metabolism in alcoholics.     

Alcohol abuse and dependence symptoms: A multidimensional model of common and specific etiology.

This study tested a theoretical model hypothesizing differential pathways from 5 predictors to alcohol abuse and dependence symptoms. The participants were college students (N = 2,270) surveyed on 2 occasions in a 6-month prospective design. Social norms, perceived utility of alcohol use, and family history of alcohol problems were indirectly associated with Time 2 abuse and dependence symptoms through influencing level of alcohol consumption. Poor behavioral control had a direct effect on alcohol abuse but not on dependence symptoms at Time 2, whereas affective lability exhibited a direct prospective effect on alcohol dependence but not on abuse symptoms. A multigroup analysis showed that high levels of poor control increased the strength of paths from both consumption level and affective lability to abuse symptoms. Implications for prevention of alcohol problems among college students are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Social and behavioral consequences of alcohol consumption and expectancy: A meta-analysis.

Conducted a meta-analysis on 34 studies that investigated the effects of alcohol consumption and expectancy within the balanced-placebo design. Preliminary results indicated that both alcohol and expectancy had significant but heterogeneous effects on behavior. Subsequent analyses were conducted to determine the factors responsible for the heterogeneity of effects. At the highest level of analysis, alcohol expectancy had strong effects on relatively deviant social behaviors and minimal effects on nonsocial behaviors. Alcohol consumption showed the opposite pattern of effects. The principal effects associated with alcohol expectancy involved increased alcohol consumption and increased sexual arousal in response to erotic stimuli. On the other hand, alcohol consumption led to significant impairment of information processing and motor performance, induced a specific set of physical sensations, resulted in general improvements of mood, and tended to increase aggression. Across all studies it was observed that alcohol consumption and expectancy interacted no more frequently than would be expected by chance. A list of the studies used in the meta-analysis is appended. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human mu-opioid receptor variation and alcohol dependence

Mu-Opioid receptor-mediated neurotransmission is involved in the reward, tolerance, and withdrawal effects of alcohol. The present association study tested the hypothesis that the common Asn40Asp substitution polymorphism in the N-terminal domain of the human mu-opioid receptor (OPRM) confers vulnerability to subtypes of alcohol dependence. The genotypes of the Asn40Asp substitution polymorphism were assessed in 327 German alcohol-dependent subjects (according to ICD-10) and in 340 control subjects of German descent, using an assay based on allele-specific polymerase chain reaction. To select alcoholics with a presumed high genetic load, three subgroups were delineated, marked by (1) a family history of parental alcoholism (n = 114); (2) the inability to abstain from alcohol before the age of 26 years (n = 73); and (3) a history of alcohol withdrawal seizure or delirium (n = 107). The frequency of the Asp40 allele did not differ significantly between the controls [f(Asp40) = 0.078] and either the entire group of alcoholics [f(Asp40) = 0.107; p = 0.066], or the alcoholics with parental alcoholism [f(Asp40) = 0.114; p = 0.094], or the early-onset alcoholics [f(Asp40) = 0.096; p = 0.471,[ or the alcoholics with severe withdrawal symptoms [f(Asp40) = 0.098; p = 0.350]. Our results do not provide evidence that the common Asn40Asp substitution polymorphism of the OPRM gene contributes a major effect to the pathogenesis of alcohol dependence.     

Ca2+ activated myosin-ATPase in cardiac myofibrils of rainbow trout, freshwater turtle, and rat

The effects of natural variation in the number of copies of the growth hormone (GH) gene on growth parameters, plasma GH profiles, and the response to GHRH challenge were compared in Coopworth ram lambs from selection lines differing in body composition and GH levels. Different genotypes at the GH locus carried two, three, or four copies of the GH gene and GH secretion was studied under ad libitum feeding conditions and in the fasted state. There were no significant effects of GH genotype on any parameters of growth or body composition. Basal serum GH concentration, GH pulse frequency, and GH pulse amplitude differed significantly with selection line and fasting, but did not differ significantly between the GH genotypes. Significant differences of subtle nature were found between the GH genotypes in their responsiveness to GHRH. For the ad libitum-fed Lean selection line animals, the first GHRH challenge resulted in a higher mean maximum response for GH1/GH1 than GH2/GH2 (P < 0.05). Between the first and the second challenges there was a decrease in maximum response for the GH1/GH1 genotype and an increase for the GH2/GH2 genotype (P < 0.05 for GH genotype main effect). The differences between GH genotypes in response to GHRH challenge suggest that polymorphism in the number of GH gene copies in sheep may have physiological implications for the function of the GH axis, which may be manifested in growing lambs only under specific genotype-environment combinations.     

Genetic Associations of Alcohol Dehydrogenase With Alcohol Use Disorders and Endophenotypes in White College Students.

Associations of alcohol dehydrogenase (ADH) gene polymorphisms (ADH1B*2 and ADH1C*1) with a lifetime alcohol use disorder (AUD) were examined in White college students. Alcohol-related endophenotypes likely to be influenced by elevations in acetaldehyde were also assessed. Individuals with an ADH1B*2 allele had lower rates of AUDs, consumed a lower maximum number of drinks in a 24-hr period, reported a greater level of response to alcohol, were more likely to have experienced alcohol-induced headaches following 1 or 2 drinks, and reported more severe hangovers than those lacking this allele. These findings are consistent with the hypothesis that enhanced sensitivity to alcohol and lower levels of alcohol use reflect the mechanism by which ADH1B*2 protects against developing an AUD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factor analyses of alcohol and water consumption in laboratory mice.

Tested 99 mice from 9 different genotypes for 10 consecutive days in a 2-choice situation with drinking tubes containing water and dilute ethanol. Separate recordings of alcohol and water consumption were taken according to the light cycle, at 9:30 AM and 9:30 PM on each day. The 20 measures of alcohol and water consumption were factor analyzed separately by alpha analysis with varimax rotation. 2 factors with eigenvalues greater than 1 were obtained for alcohol and 3 for water consumption. Factors differed strikingly depending on the fluid involved. Water-consumption factors reflected the nocturnal-diurnal activity cycle. Alcohol-consumption factors were related to changes over days but not to the activity cycle. (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vitro drug sensitivity and clinical aspects of Plasmodium falciparum malaria in African children

OBJECTIVE: To compare body mass index (BMI), lipid, lipoprotein and apolipoprotein concentrations according to the Hind III and Pvu II restriction polymorphisms of the LPL gene in obese subjects. DESIGN: Cross sectional study of anthropometric and lipid variables in relation to genetic factors. SETTING: Nutrition Outpatient Clinic of Bichat Hospital in Paris, France. SUBJECTS: 236 unrelated patients (162 women and 74 men) were selected on the basis of 120% of ideal body weight. MAIN OUTCOME MEASURES: Anthropometry (body mass index, waist to hip ratio), blood lipids and lipoproteins, determination of LPL Hind III and Pvu II genotypes. RESULTS: Digestion with Hind III generated two alleles, H1 (absence of cutting site) and H2 (presence of cutting site), with frequencies of 0.30 and 0.70 respectively. Digestion with Pvu II generated two alleles P1 and P2 with frequencies of 0.49 and 0.51 respectively. The Hind III polymorphism was significantly associated with body mass index (BMI) (P < 0.05). The H2H2 genotype was associated with hypertriglyceridemia: 68% of the hypertriglyceridemic subjects have the H2H2 genotype vs 43% of the normotriglyceridemic group (P < 0.05). Plasma triglyceride levels varied significantly among the Hind III genotypes, H2H2 genotype having the highest total and VLDL-triglyceride levels; the Hind III polymorphism also showed a significant association with HDL2-cholesterol. These associations were only seen in women and were not explained by the variations in BMI and age. No significant associations were found between lipid traits and Pvu II genotype. CONCLUSION: These results suggest that genetic variation in the LPL gene in obese subjects is associated with hypertriglyceridemia and possibly with a predisposition to obesity.     

Smoking, obesity, and hypertension alter the dose-response curve and test sensitivity of carbohydrate-deficient transferrin as a marker of alcohol intake

Serum carbohydrate-deficient transferrin (CDT) is a specific and comparatively sensitive marker of excessive alcohol use; however, reports of its sensitivity vary according to the population or patient groups studied and their average alcohol intake. We have characterized the dose-response curve between alcohol intake and CDT concentrations in a study of 1400 men and women from a community-based twin registry. Our results show that mean CDT increases with increasing reported alcohol consumption even within the range of alcohol use considered to be nonhazardous. We found significant effects of sex, age, smoking, previous alcohol dependence, body mass index, and diastolic hypertension on the alcohol-CDT dose-response curve. These variables either affect test sensitivity or require adjustment of reference intervals. The results also provide insight into the physiological and biochemical factors that affect CDT concentration.     

Utility of biological markers during outpatient treatment of alcohol-dependent subjects: carbohydrate-deficient transferrin responds to moderate changes in alcohol consumption

A group of 25 alcohol-dependent subjects in outpatient treatment were monitored for a period of 4 weeks. They were weekly interviewed for their alcohol consumption and their serum levels of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltransferase (GT) were analyzed. The majority of the patients reported an excessive and fairly constant alcohol intake during the observation period. When selecting those patients that reported periods of 1 or 2 weeks with moderate changes in alcohol consumption, corresponding changes in CDT were demonstrated. Thus, of 14 patients reporting an increased alcohol consumption for 2 weeks (mean values increased from 57 to 101 g/day), 11 showed an increase in CDT at the end of the period. The mean CDT value of all 14 increased from 5.5 to 6.7% (p < 0.05). Slight, but not significant, increases were noted in GT, indicating that CDT is more sensitive than GT in detecting increased alcohol consumption. Furthermore, of 17 patients that reported decreased alcohol consumption for one or several weeks, 14 showed decreased CDT and GT values. The mean values of all 17 were reduced from 5.1% to 4.5% (CDT) and from 126 units/liter to 97 units/liter (GT) (p < 0.05 for both parameters). The results indicate that CDT responds to moderate changes in alcohol consumption in alcohol-dependent patients and may thus be useful as a corrective tool to self-reports of alcohol consumption during outpatient treatments.     

Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione S-transferase M1/T1/P1 genotypes

Isothiocyanates (ITCs), degradation products of glucosinolates (which occur naturally in a variety of cruciferous vegetables), have been shown to exhibit chemopreventive activity. These compounds are metabolized in vivo to form the corresponding dithiocarbamates, which are the major urinary metabolites of ITCs, by a pathway involving the glutathione S-transferase (GST) class of enzymes. Using a newly developed assay that measures total ITC (primarily ITC conjugates) in urine, we examined the relationships between cruciferous vegetable intake (obtained from a food frequency/portion size questionnaire administered in person); dietary total ITC level; GSTM1, GSTT1, and GSTP1 genotypes; and levels of total ITC in spot urine samples collected from 246 Singapore Chinese (111 men and 135 women), ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Consumption level of cruciferous vegetables was high in study subjects (mean consumption = 345 times per year, mean daily intake = 40.6 g), which was >3 times the comparable level of intake in the United States. Mean daily intake of total ITC among study subjects was 9.1 micromol, and there was a 2.5-fold difference between the 25th and 75th percentile values. Seventy-three % of study subjects tested positive for ITC in urine, and there was a 4-fold difference between the 25th and 75th percentile values among the positive subjects. There was a highly significant positive association between dietary intake and urinary excretion levels of total ITC (two-sided P = 0.0003) that was stronger than the association between overall cruciferous vegetable intake and urinary ITC level, which also was statistically significant (P = 0.0004). There was no difference in urinary ITC levels between GSTM1-null and GSTM1-positive study subjects (P = 0.61) or between subjects with differing GSTP1 genotypes (P = 0.77), but urinary excretion of ITC was significantly higher among GSTT1-positive subjects, relative to GSTT1-null subjects (P = 0.006). The strength of the association between GSTT1 genotype and urinary total ITC level was highly dependent on the level of cruciferous vegetable consumption (or dietary ITC level) in study subjects. Among subjects in the lowest tertile of cruciferous vegetable intake, there was little evidence of an association between GSTT1 genotype and urinary total ITC level (P = 0.67). In contrast, there was a strong and statistically significant association between GSTT1 genotype and urinary total ITC among subjects in the highest tertile of cruciferous vegetable intake (P = 0.02), whereas those in the middle tertile of cruciferous vegetable consumption exhibited an association of intermediate strength (P = 0.04). These results suggest the presence of GSTT1 inducers in cruciferous vegetables.