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PubMed2001

ALDH2 status, alcohol expectancies, and alcohol response: preliminary evidence for a mediation model.

BACKGROUND: A genetic variant in the alcohol-metabolizing enzyme (aldehyde dehydrogenase; ALDH2*2 allele), common in individuals of Asian heritage, has been associated with both physiologic response to alcohol and alcohol consumption. Prior research has also demonstrated that those with ALDH2*2 alleles have lower positive alcohol expectancies than those without these alleles. This preliminary study was designed to test whether the level of response to alcohol is the mechanism by which ALDH2 status may affect alcohol expectancies. METHODS: Data were collected from 32 Asian American college students (14 women and 18 men). By use of a randomized, double-blind design, participants were administered oral placebo and alcohol at separate laboratory sessions. Data included blood tests to establish ALDH2 status, questionnaire measures of demographic information and alcohol expectancy, and several physiologic measures collected after placebo and alcohol administration. RESULTS: ALDH2 status was related to alcohol response measures for both men and women. ALDH2 status was also related to tension reduction expectancies for women and to expectancies for cognitive behavioral impairment for men. In the male sample, the ALDH2/expectancy relationship was fully explained by the level of response to alcohol. CONCLUSIONS: These results represent a first step in understanding the mechanisms by which genetic factors, such as ALDH2 status, can affect alcohol-related learning.

Adult↗
PubMed1988

Frequency of the atypical aldehyde dehydrogenase-2 gene (ALDH2(2)) in Japanese and Caucasians.

All Caucasians have two major aldehyde dehydrogenase isozymes--i.e., the cytosolic ALDH1 and the mitochondrial ALDH2-while approximately 50% of Orientals are atypical and lack the catalytically active ALDH2 in their tissues. The atypical ALDH2(2) gene has a nucleotide base change and produces the defective ALDH2(2) protein, which has a Glu----Lys substitution at the 14th position from the COOH-terminal (Yoshida et al. 1984; Hsu et al. 1985). With the use of a pair of synthetic oligonucleotides-one complementary to the usual ALDH1(2) and the other complementary to the atypical ALDH2(2)-genotypes of 49 unrelated Japanese individuals and 12 Caucasians were determined. The frequency of the atypical ALDH2(2) allele was found to be .35 in the Japanese samples examined. The atypical ALDH2(2) gene was not found in the Caucasians.

Aldehyde Dehydrogenase↗
PubMed1995

[Association between alcoholics and the genotypes of ALDH2, ADH2, ADH3 as well as P-4502E1].

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.

Alcohol Dehydrogenase↗
PubMed1998

[Investigation for polymorphism of ALDH2 exon12 in several Asian areas].

Mitochondrial aldehyde dehydrogenase (ALDH2) shows genetic polymorphism (Glu487Lys substitution) among Mongoloid populations, and the substitution is responsible for flushing symptom after alcohol intake. Recently, new ALDH2 alleles (ALDH2*3 and ALDH2*2Taiwan) in exon12 were reported in North American Indians and in Chinese from Taiwan by Novoradskey et al (1995). In the present study, we investigated the new allelic variants in exon12 for the five different ethnic groups (Mongolian, North Chinese, South Chinese, Myanmar, Japanese) by using PCR-SSCP and PCR-direct sequencing. Also, Glu 487 Lys substitution was analyzed to obtain additional information on gene geography of ALDH2 alleles in Asia reported so far. No new variants were found in the five population groups, but ALDH2*2 allele showed different frequencies among these groups. Especially, the frequencies of ALDH2*2 in Myanmer (0.02) and Mongolian (0.05) were significantly lower than other populations.

Aldehyde Dehydrogenase↗
PubMed1997

Simple and rapid determination of the acetaldehyde dehydrogenase (ALDH2) genotypes by nonradioactive single-strand conformation polymorphism analysis.

The genotyping of mitochondrial acetaldehyde dehydrogenase (ALDH2) is very important in alcohol studies. We describe an ALDH2 genotyping method based on nonradioactive single-strand conformation polymorphism (SSCP) analysis on mini-gels following amplification with a mutated primer set. The three ALDH2 genotypes were clearly and unambiguously distinguished. This method was applied to the ALDH2 genotyping of 129 unrelated Japanese. The allele frequency of ALDH2*2 was calculated to be 0.271, which was consistent with the previous data. The method proved to be simple, rapid and reliable, and dispensed with isotopic reagent and expensive restriction enzymes and equipment. The SSCP method described here is valuable in routine ALDH2 genotyping.

Aldehyde Oxidoreductases↗
PubMed2006

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population.

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.

Adult↗
PubMed1999

Nucleotide sequence diversity in non-coding regions of ALDH2 as revealed by restriction enzyme and SSCP analysis.

The simultaneous analysis of closely linked nucleotide substitutions has recently become possible. However, it is not known whether the construction of molecular haplotypes will be a generally useful strategy for nuclear genes. Furthermore, whereas mobility-shift methods are widely used for the discovery of nucleotide substitutions, the yield of these methods has rarely been evaluated. This paper investigates these issues in non-coding regions of ALDH2, the gene that encodes aldehyde dehydrogenase 2 (ALDH2). Screening 20 Europeans, 20 native Americans, and 20 Asians by using restriction enzyme and single-strand conformation polymorphism (SSCP) analysis has revealed 16 variable sites. SSCP yields slightly fewer than the number of nucleotide substitutions predicted by the restriction enzyme digests. Estimates of nucleotide diversity are similar to those of other genes, suggesting that the pattern of polymorphism in ALDH2 offers a preview of what can be expected in many human nuclear genes. Eight of the variable sites discovered here and four sites discovered by others have been genotyped in 756 people from 17 populations across five continents. An expectation-maximization method has used to estimate haplotype states and frequencies. Only three haplotypes are common worldwide, and a fourth haplotype is common in, but private to, Asia. Although allele frequencies differ among sites, linkage disequilibrium is almost maximal across ALDH2. This suggests that haplotype construction at ALDH2 is particularly successful. The ALDH2 result, in conjunction with linkage disequilibrium results from other genes, indicates that haplotype construction will be a generally useful genomic strategy.

Aldehyde Dehydrogenase↗
PubMed2006

Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling.

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.

Acetaldehyde↗
PubMed2001

Alcoholism, ALDH2*2 allele and the A1 allele of the dopamine D2 receptor gene: an association study.

The inactive form of aldehyde dehydrogenase-2 (ALDH2) is regarded as a protective factor against the development of alcoholism, and alcoholics with inactive ALDH2 are considered to be relatively homogeneous. This examination of a possible allelic association of the dopamine D2 receptor (DRD2) gene TaqI A polymorphism failed to detect significant differences between 583 Japanese alcoholics and 295 unrelated Japanese controls, or between alcoholic subjects with different ALDH2 genotypes. Despite the significantly higher frequency of the DRD2 A1 allele in the 207 alcoholics with inactive ALDH2 than in the 376 alcoholics with active ALDH2, multiple logistic regression analysis (controlled for the ALDH2 genotype) revealed no association between the TaqI A polymorphism and alcoholism. Nor did the frequency of the DRD2 TaqI A polymorphism differ in alcoholic subjects grouped by several pertinent clinical characteristics, including severity of alcoholism. Although there remains a possibility that the DRD2 TaqI A polymorphism plays some role in modifying the phenotype of the disease, these results suggest that neither the A1 allele nor the homozygous A1 genotype is associated with alcoholism.

Adult↗
PubMed2000

Integrating biological and behavioral factors in alcohol use risk: the role of ALDH2 status and alcohol expectancies in a sample of Asian Americans.

Prior studies have shown that the ALDH2*2 genetic variant, most common in individuals of Asian descent, is related to heightened sensitivity to alcohol and can serve as a protective factor against alcohol problems. This study explored the effect of this factor on alcohol expectancies. It was hypothesized that (a) individuals with ALDH2*2 alleles would have lower positive expectancies and higher negative expectancies, (b) expectancies would mediate the ALDH2-drinking relation, and (c) ALDH2 status would moderate the expectancy-drinking relation. Data were collected from 171 Asian American university students. Positive expectancy and ALDH2 status were correlated with alcohol use. Mediation and moderation hypotheses were supported only in the female sample. Results were not significant for negative expectancies. These results indicate that ALDH2 status may protect against drinking by lowering positive expectancies and reducing the expectancy-drinking relationship.

Adult↗
PubMed2004

Overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene prevents acetaldehyde-induced cell injury in human umbilical vein endothelial cells: role of ERK and p38 mitogen-activated protein kinase.

Acetaldehyde, the major ethanol metabolite that is far more toxic and reactive than ethanol, has been postulated to be responsible for alcohol-induced tissue and cell injury. This study was to examine whether facilitated acetaldehyde metabolism affects acetaldehyde-induced oxidative stress and apoptosis. Transgene-encoding human aldehyde dehydrogenase-2 (ALDH2), which converts acetaldehyde into acetate, was constructed under chicken beta-actin promoter and transfected into human umbilical vein endothelial cells (HUVECs). Efficacy of ALDH2 transfection was verified using green fluorescent protein and ALDH2 enzymatic assay. Generation of reactive oxygen species (ROS) was measured using chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride fluorescence microscopy, quantitative DNA fragmentation, and caspase-3 assay. Acetaldehyde (0-200 microm) elicited ROS generation and apoptosis in HUVECs in a time- and concentration-dependent manner, associated with activation of the stress signal molecules ERK1/2 and p38 mitogen-activated protein (MAP) kinase. A close liner correlation was observed between the acetaldehyde-induced ROS generation and apoptosis. Interestingly, the acetaldehyde-induced ROS generation, apoptosis, activation of ERK1/2, and p38 MAP kinase were prevented by the ALDH2 transgene or antioxidant alpha-tocopherol. The involvement of ERK1/2 and p38 MAP kinase in acetaldehyde-induced apoptosis was confirmed by selective kinase inhibitors U0126, SB203580, and SB202190. Collectively, our data revealed that facilitation of acetaldehyde metabolism by ALDH2 transgene overexpression may prevent acetaldehyde-induced cell injury and activation of stress signals. These results indicated therapeutic potential of ALDH2 enzyme in the prevention and detoxification of acetaldehyde or alcohol-induced cell injury.

Acetaldehyde↗
PubMed1995

CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese.

The genotypes of the CYP2E1 and ALDH2 loci of alcoholic (alcohol dependence) and nonalcoholic (healthy) Japanese were investigated to examine the relationship between the polymorphism of CYP2E1 (C1/C2) and ALDH2 (ALDH2*1/ALDH2*2), and the susceptibility to alcoholism. There was no significant difference in C2 gene frequency between alcoholics (0.19) and nonalcoholics (controls) (0.20), whereas there was a significant difference in ALDH2 allele frequency, suggesting that, in Japanese, the C2 genotype of CYP2E1 may have nothing to do with the risk of developing alcohol dependence. However, the ALDH2*1 allele may influence drinking behavior and the development of alcohol dependence. Furthermore, racial interethnic differences in the frequency of the mutated allele of the CYP2E1 gene (C2) were found, like the ALDH2 gene. Japanese healthy controls showed a significantly higher frequency of the C2 allele than did Swedish healthy controls (0.05; reported by Persson et al., FEBS Lett. 319:207-211, 1993).

Alcohol Drinking↗
PubMed2006

ALDH2 1510 G/A (Glu487Lys) polymorphism interaction with age in head and neck squamous cell carcinoma.

Recent molecular epidemiological studies have revealed a possible association of the acetaldehyde dehydrogenase-2 (ALDH2) 1510 G/A (Glu487Lys) polymorphism with various cancers including head and neck squamous cell carcinoma (HNSCC). To further elucidate the significance of this polymorphism in HNSCC development, the relationship between ALDH2 1510 G/A and clinicopathological parameters, cigarette smoking or alcohol intake was evaluated in patients with HNSCC. DNA samples from 192 patients with primary HNSCC and 192 age- and gender-matched healthy controls were genotyped and statistically evaluated. Although there was no significant difference in the genotype distribution of ALDH2 1510 G/A between cases and controls, we found that the frequency of the ALDH2 genotypes with the mutated A (Lys) allele was greater in patients aged <66 years than in those aged > or = 66 years (p = 0.034). This tendency became more evident in patients with the habit of drinking (n = 143; p = 0.009). The association of ALDH2 1510 G/A with age remained significant after multivariate logistic regression analysis was performed for the patients (odds ratio for an age interval for 1 year, 0.970; 95% confidence interval, 0.943-0.998). The present data suggest a possible interaction between the ALDH2 1510 G/A polymorphism and age in HNSCC.

Age Factors↗
PubMed2000

Hangover symptoms in Asian Americans with variations in the aldehyde dehydrogenase (ALDH2) gene.

OBJECTIVE: Hangovers are not experienced by all people and whether they contribute to the development of alcoholism is unclear. One population that might provide some insight into the role of hangover in the etiology of alcohol use disorders is that of individuals of Asian heritage. Certain Asians have lower rates of alcohol use and alcoholism, findings associated with a mutation in the aldehyde dehydrogenase (ALDH2) gene. Asians with ALDH2*2 alleles drink less and are less likely to be alcoholic than Asians without this mutation. Following alcohol ingestion, they exhibit more intense reactions to alcohol and generate higher levels of the metabolite acetaldehyde. This study evaluated hangover symptoms in Asian Americans with variations in the ALDH2 gene. METHOD: Men and women of Chinese, Japanese and Korean heritage (N = 140) were asked about their drinking history and a blood sample was collected for genotyping at the ALDH2 locus. Subjects used a Likert-type scale to estimate their severity of hangover and completed a 13-item hangover scale assessing the frequency of hangover symptoms during the previous 6 months. RESULTS: With abstainers (n = 17) excluded and with the effects of gender and recent drinking history controlled, ALDH2 genotype accounted for a significant amount of additional variability in the estimated severity of hangover score with a similar, but nonsignificant, trend for a five-item subscale score derived from the hangover scale. CONCLUSIONS: These results suggest that Asian Americans with ALDH2*2 alleles may experience more severe hangovers that may contribute, in part, to protection against the development of excessive or problematic drinking in this population.

Adult↗
PubMed2006

Application of aldehyde dehydrogenase 2 (ALDH2) genetic diagnosis in support of decreasing alcohol intake.

Encouraging behavioral changes to decrease alcohol intake is not easy from the standpoint of health support. This study was conducted to examine whether the genetic diagnosis of ALDH2 polymorphism is useful in supporting those who want to decrease their alcohol intake. The participants in this study were 329 male employees who wanted to know the result of their ALDH2 genotype. We divided the 329 participants randomly into two groups. One was the "notified group" (n=157), and the other was the "non-notified group" (n=172). The subjects belonging to the "notified group" were informed of the results of the ALDH2 genotype diagnosis in April, 2003. Drinking habits and laboratory data were obtained before and after notification of the ALDH2 genotype. Among those with genotype ALDH2*1/*1, there was no significant change in drinking frequencies, nor was there any significant decline in liver function laboratory data in either of the groups before and after notification of the genotype. However, weekly alcohol intake tended to increase compared to that before notification. On the other hand, with regard to those with genotype ALDH2*1/*2, no significant changes in drinking frequencies or liver function laboratory data were evident in either group before and after notification of the genotype. However, the weekly alcohol intake tended to increase in the non-notified group, whereas it tended to decrease in the notified group. Although the result was not significant, it is suggested that, with further study and an increased sample size, the genetic diagnosis may be found to be useful.

Alcohol Drinking↗
PubMed2002

[Studies of genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang China].

In order to investigate genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City,portions of exon 3 of ADH2 and exon 12 of ALDH gene were amplified by using polymerase chain reaction. The amplified products were electrophoresed on 10% undenatured vertical polyacrylamide gels and stained with argentine. Frequencies of ADH2*1 and ADH2*2 alleles are 42.86% and 57.14%. Frequencies of three genotypes of ADH2 are 22.86%,40.00% and 37.14%,respectively. Frequencies of ALDH2*1 and ALDH2*2 alleles are 85.24% and 14.76%. Genotype frequencies of ALDH2 loci are 71.43%,27.62% and 0.95%,respectively. Genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City are different from those among Taiwanese and Shanghainese. Frequency of ALDH2*1/*1 in Luoyang people is higher than those in Shanghai and Taiwan. Therefore,there is a higher resistance to alcohol drinking in the Han population in Luoyang.

English Abstract↗
PubMedDate not supplied

Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions.

Alcohol drinking is a major risk factor for esophageal cancer in Japan and its impact may be modulated by levels of ALDH2, ADH2 and CYP2E1, three representative alcohol-metabolizing enzymes which display genetic polymorphisms altering individual alcohol-oxidizing capacity and drinking behavior. To assess the actual influence of ADH2 Arg47His, ALDH2 Glu487Lys and CYP2E1 variant c2 allele polymorphisms on esophageal cancer risk with conjunction with alcoholic consumption, the present 1:3 matched case-control study was conducted. The 165 histologically diagnosed Japanese esophageal cancer cases were here compared with 495 randomly selected controls, matched with respect to sex and age. Conditional logistic regression was used to calculated Odds Ratios (ORs) and 95% confidence intervals (95% CI). Significant gene-environment interactions between alcohol drinking and both ADH2 and ALDH2 were observed regarding esophageal cancer risk. The ADH2 Arg47His polymorphism showed moderately increased risk (OR for Arg/His and Arg/Arg relative to His/His: 2.01 (1.39-2.90)). In the ALDH2 case, comparing the Glu/Lys with the Glu/Glu genotype, ORs were markedly increased to 9.64 (3.23-28.8) and 95.4 (28.7-317) from 1.88 (0.42-8.37) and 4.62 (0.93-23.1) for moderate drinking and heavy drinking, respectively. No significant alteration in risk was observed with the CYP2E1 polymorphism. In conclusion, the present study revealed a significant gene-environment interaction between alcohol drinking and the ALDH2 polymorphism regarding esophageal cancer risk among a general population in Japan, providing concrete evidence of a role for acetaldehyde in neoplastic development. Interactions between ALDH2 and ADH2 need further clarification.

Aged↗
PubMed2005

[Effects of ethanol ingestion on glucose tolerance in people with different genotypes of ALDH2].

Effects of alcohol drinking on glucose tolerance were investigated in male healthy subjects (20-36 years old) with different phenotypes of aldehyde dehydrogenase 2 (ALDH2). Oral glucose tolerance test was performed in each subject twice with and without simultaneous oral ingestion of ethanol. Simultaneous oral ingestion of ethanol (10 g) significantly enhanced the early increase in plasma insulin concentration at 30 min after ingestion of glucose (100 g) in subjects with normal ALDH2 phenotype, while the increase in early insulin response due to alcohol was slight and not significant in those with atypical ALDH2. On the other hand, the early increase in plasma glucose concentration at 30 min after glucose inges-tion was not affected by simultaneous ethanol drinking in both groups of subjects with normal and atypical ALDH2 phenotypes. Thus, drinking alcohol together with a simple sugar causes enhancement of early insulin response, which is more prominent in people with normal ALDH2 phenotype than in those with atypical ALDH2 phenotype.

Adult↗