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PubMed2000

Fatal acute alcohol intoxication in an ALDH2 heterozygote: a case report.

On an evening in November, a 25-year-old man was found dead in his bedroom. There were many empty snap-out sheets for flunitrazepam tablets in the trash at his bedside. He had been beaten by a gang of young people earlier in the morning of the same day. At the medico-legal autopsy, although there were many bruises and/or abrasions on the whole body, only slight subdural hemorrhage was observed, and none of them was thought to be the cause of death. Flunitrazepam and its metabolites were not detected in his body fluid by gas chromatography-mass spectrometry (GC-MS). Marked lung edema and a severe congestion of organs were observed. His blood alcohol concentration from the femoral vein was 2.00 mg/ml. Fatal cases of acute alcohol intoxication usually have shown higher alcohol concentration (2.25-6.23 mg/ml). Although the genotype of aldehyde dehydrogenase 2 (ALDH2) has not previously been mentioned as a contributing factor in determining the cause of death, in this case the genotype of ALDH2 was ALDH2*1/2 and thus is important. Those who possess the ALDH2*2 gene show high concentrations of acetaldehyde (AcH) at even comparatively lower alcohol levels. Consequently, the cause of death was considered to be acute alcohol intoxication including AcH poisoning.

Acetaldehyde↗
PubMed2006

Increased DNA damage in ALDH2-deficient alcoholics.

Drinking alcohol is a risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus. Although many studies suggest that acetaldehyde, a major metabolite of orally ingested alcohol, plays a crucial role in cancer initiation, the link between the aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage has not yet been explored. We have developed a sensitive and quantitative method for detecting the acetaldehyde-derived DNA adducts, N(2)-ethyl-2'-deoxyguanosine (N(2)-Et-dG), alpha-S- and alpha-R-methyl-gamma-hydroxy-1,N(2)-propano-2'-deoxyguanosine (alpha-S-Me-gamma-OH-PdG and alpha-R-Me-gamma-OH-PdG), and N(2)-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N(2)-Dio-dG), by using liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) and stable-isotope internal standards. We determined the DNA adducts in 44 blood DNA samples from Japanese alcoholic patients. The levels of three acetaldehyde-derived DNA adducts, N(2)-Et-dG, alpha-S-Me-gamma-OH-PdG, and alpha-R-Me-gamma-OH-PdG, were significantly higher in alcoholics with the ALDH2 1/2 2 genotype compared to those with the ALDH2 1/2 1 genotype. N(2)-Dio-dG was not detected in any of the DNA samples analyzed. These results provide molecular evidence that the ALDH2 genotype affects the genotoxic damage caused by acetaldehyde.

Acetaldehyde↗
PubMed2004

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.

Adult↗
PubMed1995

Acute effects of alcohol on P300 in Asians with different ALDH2 genotypes.

Asian men were genotyped for alleles of aldehyde dehydrogenase (ALDH2) and tested on two separate occasions following oral administration of placebo and 0.75 ml/kg alcohol. Sixty minutes after beverage ingestion, event-related potentials were elicited using an auditory oddball paradigm. Repeated measures ANOVA revealed that alcohol produced significant increases in P300 latency and significant decreases in P300 amplitude compared with placebo. Subjects with ALDH2*1/2*2 genotype (n = 14) demonstrated some significantly greater P300 effects after alcohol than subjects with ALDH2*1/2*1 genotype (n = 15), despite equivalent blood alcohol concentrations. These data suggest that neurocognitive functioning may be more impaired following alcohol in subjects with an ALDH2*2 allele. These findings further suggest that a genetically controlled factor (deficiency in ALDH enzyme activity) might contribute to a decreased likelihood of alcohol intake and protection from alcoholism, because of an enhanced sensitivity to alcohol.

Adult↗
PubMed2006

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin.

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2--resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes--is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

Administration, Sublingual↗
PubMed2002

Aldehyde dehydrogenase 2 (ALDH2) genotype affects rectal cancer susceptibility due to alcohol consumption.

BACKGROUND: Epidemiologic studies have shown the association between alcohol consumption and colorectal cancer, especially for rectal cancer. The alcohol related enzyme encoding gene ALDH2 has polymorphism Glu487Lys, and 487Lys allele is closely linked with phenotypic loss of enzyme activity. MATERIALS AND METHODS: A hospital-based case-control study was conducted with 72 colon and 70 rectal cancer cases and 241 non-cancer controls to evaluate the alcohol consumption and ALDH2 Glu487Lys polymorphism. The logistic regression model was applied to estimate the odds ratios (ORs). RESULT: The crude ORs for Glu/Lys and Lys/Lys genotype relative to Glu/Glu for colon and rectal cancer were not statistically significant. However, with the rectal cancer analysis, the ORs for high alcohol consumption were greater with 487Glu/Lys genotype compared with Glu/Glu, albeit not. CONCLUSIONS: These observations suggested rectal cancer risk might be influenced by ALDH2 gene polymorphism. The prevention effect by alcohol reduction might differ by ALDH2 genotype.

Adult↗
PubMed1999

An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase (ALDH2): effects of the sequence variant on transcription factor binding and promoter strength.

INTRODUCTION: The strong protective effect of the ALDH2*2 mutation on risk of alcoholism suggests that other mutations that reduce mitochondrial aldehyde dehydrogenase (ALDH) activity in the liver might also deter drinking. This study describes a polymorphic locus found in the promoter of the ALDH2 gene that affects expression of reporter constructs. METHODS: Polymerase chain reaction (PCR)-based sequencing was used to search for polymorphisms. The ability of the promoter variants to bind transcription factors apolipoprotein A regulatory protein 1 (ARP-1) and chicken ovalbumin upstream promoter-transcription factor (COUP-TF) was tested in gel retardation assays using in vitro synthesized transcription factors. The variant promoters were tested for transcriptional activity using a heterologous promoter system and transient transfection assays. RESULTS: A common polymorphism (A or G) in the human ALDH2 promoter region was found at -361 base pair (bp) from the translation start site. This polymorphism was found at different frequencies in African Americans, Caucasians, and Asians. The polymorphism occurs adjacent to the core binding motif for the transcription factors COUP-TF and ARP-1. Competition and binding affinity determinations did not show differences in the ability of these two sequences to bind the factors. Reporter genes containing these elements upstream of a basal thymidine kinase promoter had similar activity when transfected into a fibroblast (CV-1) cell line. However, the reporter containing the G allele was more active than that containing the A allele in hepatoma (H4IIEC3) cells. CONCLUSIONS: The -361 bp A/G polymorphism is common in all racial groups tested. The G allele was more active than the A allele in a transfection assay. The basis for this difference is not known. If the differences in activity of the promoter constructs were paralleled by differences in ALDH2 enzyme activity in the liver, this polymorphism could affect risk of alcoholism.

Aldehyde Dehydrogenase↗
PubMed2004

[Aldehyde dehydrogenase (ALDH2) polymorphism and drinking behavior].

An atypical allele (ALDH2*2) in low K(m) aldehyde dehydrogenase (ALDH2), which is highly prevalent in Asians, may influence drinking behavior because of higher production of acetaldehyde in the liver. High alcohol sensitivity such as flushing after drinking has been shown to be mainly due to the atypical ALDH2 genotypes. The atypical allele is associated with alcohol-induced liver injury and some cancers. Recently, the researches on the polymorphisms not only in the gene itself but also its frequencies in different Asian populations have been made great progress. Three factors, including different sex, age and geography, were also analyzed with the genotypes of ALDH2 in Chinese populations.

Alcohol Drinking↗
PubMed1987

Direct detection of usual and atypical alleles on the human aldehyde dehydrogenase-2 (ALDH2) locus.

A method for determining human mitochondrial aldehyde dehydrogenase (ALDH2) genotypes was developed. Two 21-base synthetic oligonucleotides, one complementary to the usual ALDH2(1) gene and the other complementary to the atypical ALDH2(2) gene, were used as specific probes for in-gel hybridization analysis of human genomic DNA from either peripheral blood cells or livers. Under appropriate hybridization conditions, these two probes can hybridize to their specific complementary alleles and thus allow the genotyping of the ALDH2 locus.

Aldehyde Dehydrogenase↗
PubMed2007

Ascertainment bias and the pattern of nucleotide diversity at the human ALDH2 locus in a Japanese population.

Many East Asian human populations harbor a high-frequency deficiency allele for the aldehyde dehydrogenase 2 (ALDH2) enzyme, a critical protein involved in the metabolism of ethanol. Here we use resequencing and long-range SNP haplotype data from a Japanese sample to test whether patterns of nucleotide diversity and linkage disequilibrium at this locus are compatible with a standard neutral model of evolution. Examination of the pattern of polymorphism at a locus such as this, where the frequency of a common allele is known a priori, introduces an ascertainment bias that must be corrected for in analyses of the frequency spectrum of polymorphisms. We apply a flexible and generally applicable simulation approach to correct for this bias in our ALDH2 data and, also, to explore the effect of bias on the commonly used summary statistics Tajima's D, Fu and Li's D, and Fay and Wu's H. Our study finds no evidence that the pattern of genetic variation at ALDH2 differs from that expected under a standard neutral model. However, our general examination of ascertainment bias indicates that a priori knowledge of segregating alleles greatly affects the expected distributions of summary statistics. Under many parameter combinations we find that ascertainment bias introduces an elevated rate of false positives when summary statistics are used to test for deviations from a standard neutral model. However, we also show that over a wide range of conditions the power of all summary statistics can be greatly increased by incorporating prior knowledge of segregating alleles.

Aldehyde Dehydrogenase↗
PubMed2004

The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination.

The catalytic deficiency of human aldehyde dehydrogenase 2 (ALDH2) is caused by a nucleotide substitution (G1510A; Glu487Lys) in exon 12 of the ALDH2 locus. This SNP, and four non-coding SNPs, including one in the promoter, span 40 kb of ALDH2; these and one downstream STRP have been tested in 37 worldwide populations. Only four major SNP-defined haplotypes account for almost all chromosomes in all populations. A fifth haplotype harbours the functional variant and is only found in East Asians. Though the SNPs showed virtually no historic recombination, LD values are quite variable because of varying haplotype frequencies, demonstrating that LD is a statistical abstraction and not a fundamental aspect of the genome, and is not a function solely of recombination. Among populations, different sets of tagging SNPs, sometimes not overlapping, can be required to identify the common haplotypes. Thus, solely because haplotype frequencies vary, there is no common minimum set of tagging SNPs globally applicable. The Fst values of the promoter region SNP and the functional SNP were about two S.D. above the mean for a reference distribution of 117 autosomal biallelic markers. These high Fst values may indicate selection has operated at these or very tightly linked sites.

Aldehyde Dehydrogenase↗
PubMed2006

Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence.

The set of alcohol-metabolizing enzymes has considerable genetic and functional complexity. The relationships between some alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes and alcohol dependence (AD) have long been studied in many populations, but not comprehensively. In the present study, we genotyped 16 markers within the ADH gene cluster (including the ADH1A, ADH1B, ADH1C, ADH5, ADH6, and ADH7 genes), 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals. Associations between markers and disease were analyzed by a Hardy-Weinberg equilibrium (HWE) test, a conventional case-control comparison, a structured association analysis, and a novel diplotype trend regression (DTR) analysis. Finally, the disease alleles were fine mapped by a Hardy-Weinberg disequilibrium (HWD) measure (J). All markers were found to be in HWE in controls, but some markers showed HWD in cases. Genotypes of many markers were associated with AD. DTR analysis showed that ADH5 genotypes and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2 were associated with AD in European Americans and/or African Americans. The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well-known functional variants. We demonstrated that DTR was more powerful than many other conventional association methods. We also found that several ADH genes and the ALDH2 gene were susceptibility loci for AD, and the associations were best explained by several independent risk genes.

Adult↗
PubMed1992

Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles.

Asian-American men who possess ALDH2*2 alleles and who experience a facial flush after consuming alcohol were carefully matched on drinking history and demographic variables with nonflushing Asian males with only ALDH2*1 alleles. Each man was tested following placebo and a challenge dose of 0.75 ml/kg alcohol. Following alcohol, flushers reported experiencing significantly more positive feelings of intoxication than nonflushers, despite equivalent blood alcohol concentrations. These data suggest that Asians who flush after drinking, particularly those with ALDH2*1/2*2 genotype, have a more intense, although not necessarily a more negative, response to alcohol than comparable nonflushing Asians. This alcohol sensitivity reaction that many Asian flushers experience may contribute to their lower tendency to drink excessively, even though their response to alcohol is not predominantly negative.

Adult↗
PubMedDate not supplied

Absence of the atypical mitochondrial aldehyde dehydrogenase (ALDH2) isozyme in Saskatchewan Cree Indians.

Three methods were employed to assess whether human volunteers (Caucasian, Asian or Cree Indian) possessed the typical or atypical mitochondrial aldehyde dehydrogenase (ALDH2) isozyme. These methods were: (1) questioning individuals about facial flushing responses following alcohol consumption; (2) application of the ethanol skin patch test, and (3) direct analysis using isoelectric focusing and activity staining of ALDH activity in hair root samples. The results from the three methods were in good agreement and revealed that only the typical ALDH2 isozyme was expressed in Saskatchewan Cree Indians. In agreement with previous reports, the typical ALDH2 was expressed in the Caucasian group of subjects, while both the typical and atypical forms were expressed in the Asian subjects.

Alcohol Drinking↗
PubMed1996

Alcohol-metabolising genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3 and ALDH2.

BACKGROUND: Previous population association studies have indicated that certain alleles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) may reduce the risk of alcoholism in Asian populations. The association of ALDH2 and ADH2 with the development of alcoholism was found to be independent of each other and has been replicated in different Asian populations, while the effect of ADH3 is less studied. METHOD: We genotyped the alcohol metabolism genes among Han men with alcohol dependence (n = 46) and their ethnically matched normal controls (n = 63) in Taiwan. Multiple logistic regression was then applied to assess the contribution of ADH3 to alcoholism by controlling the effect of ALDH2 and ADH2. RESULTS: The results of multivariate analyses demonstrated that the odds ratios for an increment of one allele of ADH2*1, ADH3*2 and ALDH2*1 in the development of alcoholism were 4.18, 3.82, and 6.89, respectively. CONCLUSIONS: These findings clearly indicate that all three alcohol-metabolising genes contribute to susceptibility to alcoholism.

Adult↗
PubMed1999

An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans.

OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided.

Adult↗
PubMed2005

[Consciousness survey regarding genetic diagnosis of glutathione S-transferase M1 (GSTM1) and aldehyde dehydrogenase 2 (ALDH2) polymorphism].

A Consciousness survey regarding genetic diagnosis of GSTM1 and ALDH2 was performed to evaluate the potential use of such a diagnosis in supporting those wanting to stop smoking and decrease alcohol intake. A questionnaire was given to 1,654 employees (male: 1,225, female: 429) who worked at an LSI manufacturing factory, and 1,434/1,654 (86.7%) responded to the survey. The number of respondents who replied that they "wanted to know the results of the genetic diagnosis of GSTM1 and ALDH2" were 731/1,401 (52.2%) and 812/1,434 (56.6%), respectively while the numbers of respondents who replied that they "did not want to know the results" were 138/1,401 (9.9%) and 103/1,434 (7.2%), respectively. The main reasons given for wanting to know the results of the genetic diagnosis of their enzymes reflected the respondents' awareness of their genetic susceptibility. These reasons included a desire to know the effects of tobacco smoke, to prevent diseases in the future, to know the effects of passive smoking or to know their tolerance for alcohol. On the other hand, the main reason for not wanting to know the genetic results that the respondents had no intention of stopping smoking and heavy drinking, or that they would be unable to stop even if they knew the results of the genetic diagnosis. Multiple regression analysis showed that the number of respondents who "wanted to know the results of the genetic diagnosis" was significantly higher among those respondents who are current smokers (male: OR = 1.66 95%CI 1.29-2.14, female: OR = 2.33 95%CI 1.37-3.98), those who understood the relationship between smoking and lung cancer (male: OR = 1.81 95%CI 1.25-2.63, female: OR = 2.77 95%CI 1.42-5.40) and those who with a high CAGE test score (male: OR = 1.96 95%CI 1.42-2.68, female: OR = 2.52 95%CI 1.07-5.94). The results of this survey suggest that genetic diagnosis of GSTM1 and ALDH2 polymorphism may be useful in supporting those who want to stop smoking and decrease their alcohol intake.

Adult↗
PubMed1994

[A characteristic of alcoholics with the atypical aldehyde dehydrogenase (ALDH2(2)--a relationship to other alcohol metabolizing enzymes].

The series were composed of 59 alcoholics. All the subjects fulfilled the DSM-III-R criteria for alcohol dependency. We investigated the genotype at ALDH2. 6 patients were heterozygous ALDH2(1)/ALDH2(2). We determined the genotypes at ADH2, ADH3 and P-4502E1 about 6 patients. 5 patients had ADH2(1)/ADH2(1) allele. 2 patients had P-450E1*C2. We found a genetic characteristic about alcoholics with the heterozygous ALDH2(1)/ALDH2(2) allele.

Alcohol Dehydrogenase↗