ADH1B Genotypes Research Articles

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

ObjectiveFirst, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk.MethodsWe conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011.ResultsCompared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10–0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33–0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12–0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98–1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90–1.27; p for heterogeneity: 0.098)].ConclusionThe well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation.

ADH1B Polymorphism, Alcohol Consumption, and Binge Drinking in Slavic Caucasians: Results from the Czech HAPIEE Study

Several genetic polymorphisms influence the risk of heavy alcohol consumption but it is not well understood whether the genetic effects are similar in different populations and drinking cultures, nor whether the genetic influences on binge drinking are similar to those seen for alcoholism. We have analyzed the effect of the Arg47His (rs1229984) variant within the alcohol dehydrogenase (ADH1B) gene on a range of drinking related variables in a large Eastern European Slavic population (Czech HAPIEE study), which recruited random samples of men and women aged 45-69 years in 7 Czech towns (3,016 males and 3,481 females with complete data). Drinking frequency, annual alcohol intake, prevalence of binge drinking (≥100 g in men and ≥60 g in women at least once a month) and the mean dose of alcohol per occasion were measured by the graduated frequency questionnaire. Alcohol intake in a typical week was used to define heavy drinking (≥350 g/wk in men and ≥210 g in women). Problem drinking (≥2 positive answers on CAGE) and negative consequences of drinking on different aspects of life were also measured. The frequency of the His47 allele carriers was 11%. Homozygotes in the common allele (Arg47Arg), among both males and females, had significantly higher drinking frequency, and annual and weekly intake of alcohol than His47 carriers. The odds ratio of heavy drinking in Arg47Arg homozygotes versus His47 carriers was 2.1 (95% confidence intervals 1.1-3.2) in men and 2.2 (1.0-4.7) in women. In females, but not in males, Arg47Arg homozygotes had marginally significantly higher prevalence of binge drinking and mean alcohol dose per drinking session. There was no consistent association with problem drinking and negative consequences of drinking. The ADH1B genotype was associated with the frequency and volume of drinking but its associations with binge drinking and problem drinking were less consistent.

An estimate of polymorphism of ADH1B, ALDH2, and CYP2E1 alcohol biotransformation genes in Siberian indigenous and immigrant populations

In the present article, the polymorphism of ADH1B, ALDH2, and CYP2E1 genes is studied in populations of Shors, Russians of Siberia, and progenies of mixed Russian-Shor marriages. Reliable differences between groups according to the frequency of ADH1B, ALDH2, and CYP2E1 genotypes and alleles are revealed. The article shows the high heterozygosis levels of the ADH1B and ALDH2 genes. Gene distances prove that mongrels and Shors are very close to each other (d = 0.005) and Russians of Siberia are not similar to the Russians of the Central Russia (d = 0.046).

Alcohol drinking habits, alcohol dehydrogenase genotypes and risk of acute coronary syndrome

The risk of myocardial infarction is lower among light-to-moderate drinkers compared with abstainers. Results from some previous studies, but not all, suggest that this association is modified by variations in genes coding for alcohol dehydrogenase (ADH). We aimed to test this hypothesis, including alcohol as both the amount of alcohol and the frequency of drinking. we conducted a nested case-cohort study within the Danish Diet, Cancer and Health study, including 1,645 men (770 incident cases of acute coronary syndrome from 1993-1997 through 2004 and 875 randomly selected controls). Higher alcohol intake (measured as amount or drinking frequency) was associated with lower risk of acute coronary syndrome; however, there was no evidence that these finding were modified by ADH1B or ADH1C genotypes. The importance of functional variation in alcohol dehydrogenase for the association between alcohol drinking habits and the risk of developing acute coronary syndrome, if any, is very limited.

Abstract LB-397: Shortened telomeres in subjects with heavy alcohol consumption

Abstract Background: Telomere shortening in peripheral blood lymphocytes, a marker of chromosome instability, has been associated with cancer risk. Heavy alcohol consumption has been linked with oxidative stress and inflammation, two mechanisms that accelerate telomere shortening, as well as with the risk of cancer at multiple sites. Whether alcohol drinking determines telomere shortening has never been evaluated. Objectives: To investigate the effect of alcohol drinking, as well as of single nucleotide polymorphisms in genes involved in alcohol metabolism, on telomere length. Methods: We measured relative telomere length by multiplex real-time PCR in peripheral blood lymphocyte DNA from 59 alcohol abusers and 197 controls with variable alcohol use. All subjects were non-smoking Caucasian males living in Northeastern Italy. Abusers were identified through an alcohol abuse/dependence evaluation based on a CAGE-AUDIT questionnaire. Current drinking was higher in abusers (0.04-10 drinks/day; 13 subjects [22%] consuming 4 or more drinks/day) than in controls (0-5.4 drinks/day; 7 subjects [4%] consuming 4 or more drinks/day) [p<0.0001]. Eleven (20%) abusers and 15 (8%) controls had serum -glutamyltrasferase (GGT) and/or erythrocyte mean corpuscular volume (MCV), taken as conventional biomarkers of alcohol abuse, above the clinical reference values [p=0.014]. Results: Mean lymphocyte telomere length was 0.41 (0.21-0.68) in abusers and 0.79 (0.30-4.56) in controls [p<0.0001]. In the entire study population, simple linear regression analysis showed that lymphocyte telomere length was inversely associated with the number of drinks (p=0.018) and MCV (p=0.004). The proportion of subjects with MCV and/or GGT above the clinical reference values was associated with telomere shortening only among abusers (p=0.024). Carriers of the common variant homozygous genotype (rs1229984) in the alcohol dehydrogenase ADH1B metabolic gene were more likely to be abusers (p=0.008), had a higher number of drinks (p=0.0003), and showed shorter lymphocyte telomere length (p=0.026). The rs698 ADHlC and rs671 aldehyde dehydrogenase ALDH2 polymorphisms were not associated with lymphocyte telomere length. Linear multiple regression analysis on the entire study population showed that both the number of drinks (p=0.004) and ADH1B genotype (p=0.01) were independently associated with lymphocyte telomere length. Conclusions: Alcohol abusers had severely shortened telomeres compared to non-abusers. The decrease in telomere length was related with alcohol drinking and ADH1B genotype in both abusers and non-abusers. Future studies are warranted to determine the role of telomere shortening in alcohol carcinogenicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-397.

Association of polymorphism in alcohol dehydrogenase and interaction with other genetic risk factors with alcoholic liver cirrhosis

The association of polymorphism of alcohol dehydrogenase ( ADH) and its interaction with genes involved in the generation and detoxification of free radicals such as cytochrome P4502E1 ( CYP2E1) and glutathione S-transferases M1 ( GSTM1) were studied with alcoholic liver cirrhosis. The study included 175 alcoholic cirrhotic patients, 140 non-alcoholic cirrhotic patients, 255 non-alcoholic controls and 140 alcoholic controls. Our data revealed that the ADH1C*1/*1 genotype exhibited significant association with alcoholic liver cirrhosis while ADH1B genotypes did not show any significant association. A much higher risk to alcoholic liver cirrhosis was observed in patients carrying a combination of wild genotypes of ADH1C ( ADH1C*1/*1) and variant genotype of ADH1B ( ADH1B*2/*2) or CYP2E1 ( CYP2E1*5B) or null genotype of GSTM1. Our data suggest a role for the interaction amongst the genes involved in metabolizing alcohol and in generating and detoxifying free radicals with susceptibility to alcoholic liver cirrhosis.

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.

Alcohol Intake, Alcohol Dehydrogenase Genotypes and Liver Damage and Disease in the Danish General Population

We tested the hypothesis that alcohol, alone and in combination with alcohol dehydrogenase (ADH) 1B and ADH1C genotypes, affects liver damage and disease in the general population. Information on alcohol intake and on liver disease was obtained from 9,080 men and women from the Copenhagen City Heart Study. Biochemical tests for the detection of liver damage were specific for alanine aminotransferase (ALT), aspartate aminotransferase (AST)-to-ALT ratio (AST/ALT), gamma-glutamyl transpeptidase (gamma-GT), albumin, bilirubin, alkaline phosphatase, coagulation factors, and erythrocyte volume. Increasing alcohol intake was associated with increasing erythrocyte volume, AST/ALT, and levels of ALT, gamma-GT, albumin, bilirubin, coagulation factors, and with decreasing levels of alkaline phosphatase. Multifactorially adjusted hazard ratios for alcoholic liver disease overall were 0.9 (95% confidence interval (CI), 0.6-1.4), 1.4 (0.8-2.5), 1.8 (0.9-3.5), and 4.1 (2.5-7.0) for an alcohol intake of 1-13, 14-20, 21-27, and > or = 28 drinks per week, respectively, compared with drinking <1 drink per week (P for trend<0.0001); the corresponding hazard ratios for alcoholic liver cirrhosis were 1.7 (0.6-4.7), 2.0 (0.8-7.1), 6.5 (2.0-21), and 13 (4.6-37) (P for trend<0.0001). ADH1B and ADH1C genotypes were not associated with and did not modify the effect of alcohol on biochemical tests or risk of liver disease. Increasing alcohol intake from none to low (1-6 drinks per week) through to moderate (7-20 drinks per week) and excessive intake (> or = 21 drinks per week) leads to stepwise increases in signs of liver damage with no threshold effect, and to an increased risk of liver disease. The minor changes in biochemical tests for low alcohol intake may not account for subclinical liver disease.

Associations ofALDH2andADH1BGenotypes With Alcohol‐Related Phenotypes in Asian Young Adults

Associations of ALDH2 and ADH1B genotypes with alcohol use have been evaluated largely using case-control studies, which typically focus on adult samples and dichotomous diagnostic outcomes. Relatively fewer studies have evaluated ALDH2 and ADH1B in relation to continuous drinking outcomes or at different developmental stages. This study examined additive and interactive effects of ALDH2 and ADH1B genotypes on drinking behavior in a mixed-gender sample of Asian young adults, focusing on continuous phenotypes (e.g., heavy episodic and hazardous drinking, alcohol sensitivity, drinking consequences) whose expression is expected to precede the onset of alcohol use disorders. The sample included 182 Chinese- and Korean-American young adults ages 18 years and older (mean age = 20 years). Effects of ALDH2, ADH1B and ethnicity were estimated using generalized linear modeling. The ALDH2*2 allele predicted lower reported rates of alcohol use and drinking consequences as well as greater reported sensitivity to alcohol. There were significant ethnic group differences in drinking outcomes, such that Korean ethnicity predicted higher drinking rates and lower alcohol sensitivity. ADH1B status was not significantly related to drinking outcomes. Ethnicity and ALDH2 status, but not ADH1B status, consistently explained significant variance in alcohol consumption in this relatively young sample. Results extend previous work by showing an association of ALDH2 genotype with drinking consequences. Findings are discussed in the context of possible developmental and population differences in the influence of ALDH2 and ADH1B variations on alcohol-related phenotypes.

Ethnic Differences in Level of Response to Alcohol Between Chinese Americans and Korean Americans

Koreans have higher rates of alcohol-use disorders and family history of alcoholism, compared with Chinese. These differences likely reflect both environmental and genetic influences. One genetically influenced characteristic that may contribute to these ethnic differences is level of response to alcohol. Variant alleles of aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH1B) genes are prevalent in individuals of Asian heritage and have been associated with an increased level of response to alcohol and a decreased risk for alcohol dependence. Additionally, a low level of response to alcohol is more common in individuals with a first-degree family history of alcoholism and is predictive of increased risk for this disorder. It also is possible that sociocultural factors have an impact on an individual's response to alcohol. The current study examined self-report level of response to alcohol, ALDH2 and ADH1B, country of origin, and family history of alcoholism in 154 Chinese- and 181 Korean-American college students. Participants were evaluated via in-person interviews and genotyped at the ALDH2 and ADH1B loci. Ethnicity was significantly related to level of response to alcohol, with Koreans having a lower self-reported level of response than Chinese. This relationship remained significant after considering the effects of gender, height, weight, quantity and frequency of alcohol consumption (over the previous 90 days), ALDH2 genotype, ADH1B genotype, country of origin, and first-degree family history of alcohol dependence. The results suggest that a low level of response to alcohol may contribute to the increased risk for alcohol abuse and dependence found in Koreans, relative to Chinese. More research is needed to determine additional factors that may be contributing to the low alcohol response and high rates of alcoholism in Koreans.

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males

To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males. A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYP2E1*c1/*c2, ALDH2*1/*2 and ADH1B *1/*1 genotypes). A total of 80 esophageal cancer cases and 480 controls were recruited. Compared with controls, cases had a greater prevalence of heavier alcohol consumption (53.8% vs 16.2%) and a higher proportion of alcohol drinkers with >30 drink-years (28.8% vs 13.5%). Heavier alcohol consumption and alcohol drinking with >30 drink-years increased the risk of ESCC, with ORs (95% CI) of 3.20 (1.32-9.65) and 1.68 (0.96-3.21). CYP2E1 (*c1/*c1), ALDH2 (*1/*2) and ADH1B (*1/*1) genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance (P=0.014; P=0.094; P=0.0001 respectively). There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2*1/*2 as well as ADH1B encoded by ADH1B *1/*1 and CYP2E1 encoded by CYP2E1 *c1/*c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 (*1/*1 genotype) as well as ADH1B (*1/*2+*2/*2) and CYP2E1 (*c1/*c2+*c2/*c2) genotypes, with a statistically significant difference; ORs (95% CI) of 8.58 (3.28-22.68), 27.12 (8.52-70.19) and 7.64 (2.82-11.31) respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (*1/*2) combined the ADH1B (*1/*1) genotype or ALDH2 (*1/*2) combined the CYP2E1 (*c1/*c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (*1/*1)+ADH1B (*1/*2+*2/*2), ALDH2 (*1/*1)+CYP2E1 (*c1/*c2+*c2/*c2) respectively , ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively. Individuals with the ADH1B combined the CYP2E1 genotype showed no synergistic interaction. In our study, we found that alcohol consumption and polymorphisms in the CYP2E1, ADH1B and ALDH2 genes are important risk factors for ESCC, and that there was a synergistic interaction among polymorphisms in the CYP2E1, ALDH2 and ADH1B genes and heavy alcohol drinking, in Chinese males living in Gansu Province, China.

Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1-30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low-to-moderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk.

Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes

Alcohol drinking habits and alcoholism are partly genetically determined. Alcohol is degraded primarily by alcohol dehydrogenase (ADH) wherein genetic variation that affects the rate of alcohol degradation is found in ADH1B and ADH1C. It is biologically plausible that these variations may be associated with alcohol drinking habits and alcoholism. By genotyping 9080 white men and women from the general population, we found that men and women with ADH1B slow vs fast alcohol degradation drank more alcohol and had a higher risk of everyday drinking, heavy drinking, excessive drinking and of alcoholism. For example, the weekly alcohol intake was 9.8 drinks (95% confidence interval (CI): 9.1-11) among men with the ADH1B.1/1 genotype compared to 7.5 drinks (95% CI: 6.4-8.7) among men with the ADH1B.1/2 genotype, and the odds ratio (OR) for heavy drinking was 3.1 (95% CI: 1.7-5.7) among men with the ADH1B.1/1 genotype compared to men with the ADH1B.1/2 genotype. Furthermore, individuals with ADH1C slow vs fast alcohol degradation had a higher risk of heavy and excessive drinking. For example, the OR for heavy drinking was 1.4 (95% CI: 1.1-1.8) among men with the ADH1C.1/2 genotype and 1.4 (95% CI: 1.0-1.9) among men with the ADH1B.2/2 genotype, compared with men with the ADH1C.1/1 genotype. Results for ADH1B and ADH1C genotypes among men and women were similar. Finally, because slow ADH1B alcohol degradation is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by ADH1B.1/1 genotype was 67 and 62% among the white population compared with 9 and 24% among the East Asian population.

Association of the Aldehyde Dehydrogenase 2 Promoter Polymorphism With Alcohol Consumption and Reactions in an American Jewish Population

Reduction in activity of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme due to genetic deficiency causes reactions related to alcohol consumption and lowers the risk of alcoholism. ALDH2*2 is the only functionally significant polymorphism of the ALDH2 gene. An additional polymorphic locus in the promoter (G to A substitution approximately 360 bp from the translation start site) may influence ALDH2 activity through effects on transcriptional activity. The A allele is predicted to be less active transcriptionally than the G allele. Therefore, we hypothesized that individuals with 1 or 2 A alleles would have exaggerated reactions to alcohol. Fifty-three Jewish college students from a Midwestern University and 76 Jewish individuals living in a large Midwestern city (all of Ashkenazi descent) were tested for associations between ALDH2*G and ALDH2*A alleles and self-reported alcohol consumption and responses to alcohol. Genotype determination was performed using PCR and slot-blot hybridization. As alcohol drinking behavior differed substantially between the college students and the general population, as well as between males and females, the analyses were performed separately in each group. The frequency of the ALDH2*A allele was 0.87 in the 129 Jewish individuals tested. Among the general Jewish population, those who were homozygous for ALDH2*A drank fewer drinks per occasion than individuals who were not homozygous for the ALDH2*A allele, but did not drink significantly less frequently. When the other covariates (ADH1B genotype, gender, and population) were controlled for, there was a marginal association between ALDH2A genotype and quantity of alcohol consumed and the number of drinks consumed before feeling drowsy. This study suggests that the ALDH2*A allele status may correlate with variations in alcohol consumption patterns among Jews, independent of the effect of ADH1B genotype.

Alcohol metabolism, alcohol intake, and breast cancer risk: a sister-set analysis using the Breast Cancer Family Registry

Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks

In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer. A multicenter hospital-based case-control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1-4). Polymorphisms of ADH1B and ALDH2 were genotyped by the method of PCR-RFLP. Individuals with ADH1B*1/*1 genotype had a 3.99-fold risk (95% CI = 2.13-7.48) of developing esophageal cancer, compared with those with ADH1B*2/*2 genotype, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99-fold risk (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, of developing esophageal cancer, compared with those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes of ADH1B and ALDH2 on esophageal cancer risk. These results suggest that ADH1B and ALDH2 polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.

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

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. 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. 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. 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.

Alcoholism and Alcohol Drinking Habits Predicted from Alcohol Dehydrogenase Genes

Alcohol drinking habits and alcoholism are partly genetically determined. Alcohol is degraded primarily by alcohol dehydrogenase (ADH) wherein genetic variation that affects the rate of alcohol degradation is found in ADH1B and ADH1C. It is biologically plausible that these variations may be associated with alcohol drinking habits and alcoholism. By genotyping 9080 white men and women from the general population, we found that men and women with ADH1B slow vs fast alcohol degradation drank more alcohol and had a higher risk of everyday drinking, heavy drinking, excessive drinking and of alcoholism. For example, the weekly alcohol intake was 9.8 drinks (95% confidence interval (CI): 9.1–11) among men with the ADH1B·1/1 genotype compared to 7.5 drinks (95% CI: 6.4–8.7) among men with the ADH1B·1/2 genotype, and the odds ratio (OR) for heavy drinking was 3.1 (95% CI: 1.7–5.7) among men with the ADH1B·1/1 genotype compared to men with the ADH1B·1/2 genotype. Furthermore, individuals with ADH1C slow vs fast alcohol degradation had a higher risk of heavy and excessive drinking. For example, the OR for heavy drinking was 1.4 (95% CI: 1.1–1.8) among men with the ADH1C·1/2 genotype and 1.4 (95% CI: 1.0–1.9) among men with the ADH1B·2/2 genotype, compared with men with the ADH1C·1/1 genotype. Results for ADH1B and ADH1C genotypes among men and women were similar. Finally, because slow ADH1B alcohol degradation is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by ADH1B·1/1 genotype was 67 and 62% among the white population compared with 9 and 24% among the East Asian population.

No Alcoholism-Protection Effects of ADH1B*2 Allele in Antisocial Alcoholics among Han Chinese in Taiwan

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. 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. 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. We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.

Associations of ALDH2 and ADH1B genotypes with response to alcohol in Asian Americans.

Individuals with alcohol dependence are less likely to possess variant alleles of the alcohol-metabolizing genes, aldehyde dehydrogenase (ALDH2*2) and alcohol dehydrogenase (ADH1B*2), than non-alcohol-dependent controls. It is hypothesized that the mechanism through which these alleles protect against alcohol dependence is by causing elevations in acetaldehyde, which in turn cause an increased response to alcohol. Previous research has shown that individuals with ALDH2*2 demonstrate enhanced reactions to alcohol compared with those without this genetic variant, but evidence that ADH1B*2 is associated with a greater alcohol response is mixed. This study was designed to determine whether the ADH1B genotype is associated with more intense reactions to alcohol after controlling for the ALDH2 genotype. Participants (N = 101) were Asian American college students. Each was evaluated using objective and subjective measures before and after ingestion of alcohol and placebo beverages. Participants with the ALDH2*1/*2 and ALDH2*2/*2 genotypes were more likely to experience vomiting following ingestion of the alcohol beverage than those with the ALDH2*1/*1 genotype. Participants with the ALDH2*1/*2 genotype also had greater pulse-rate increases, observed flushing ratings, and subjective feelings of intoxication 30 minutes after ingestion of alcohol than participants with the ALDH2*1/*1 genotype, despite equivalent blood alcohol concentration (BAC) measurements. Among participants with the ALDH2*1/*1 genotype, there were no additional effects of the ADH1B genotype on any measures of response to alcohol. Among participants with the ALDH2*1/*2 genotype, those with the ADH1B*2/*2 genotype were more likely to experience alcohol-induced vomiting and to report feeling less "great overall" 30 minutes after ingestion of alcohol than those with the ADH1B*1/*2 genotype. These findings are consistent with the hypothesis that there is an additional effect of ADH1B*2 on level of response to alcohol, but only among individuals with the ALDH2*1/*2 genotype.