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PubMed1995

Mitochondrial aldehyde dehydrogenase polymorphism in Asian and American Indian populations: detection of new ALDH2 alleles.

Genetic deficiency of the mitochondrial aldehyde dehydrogenase (ALDH2) is frequent in Asian peoples where it is an important factor negatively regulating drinking behavior. To obtain additional information on gene geography of known ALDH2 alleles, and look for new variants, ALDH2 genes were evaluated in a Chinese population from Taiwan, a Yakut population of Siberia, and in five North American Indian populations. A novel approach based on a single-strand conformation polymorphism assay, and polymerase chain reaction-directed mutagenesis was developed for genotyping. In the Taiwan Chinese population, the ALDH2(2) allele frequency was 0.319 +/- 0.025, and this allele was not detected in the Yakut population nor in the five North American Indian populations. However, a new allele, ALDH2(3), was detected in Pima Indians at a frequency of 0.044 +/- 0.022, and this allele was also observed in 1 of 49 Pueblo samples. ALDH2(3) is a silent transition 1464 G-->A, and it possibly has a wide distribution among North American Indians. A new subtype of the ALDH2(2) allele, designated as ALDH2(2Taiwan), was found in 1 of 174 Chinese from Taiwan. ALDH2(2Taiwan) is characterized by two G-->A transitions at bases 1486 and 1510, resulting in Glu-->Lys substitutions at both the 479 and 487 positions. Thus, this second nonconservative ALDH2 substitution occurs within the sequence of the already inactive ALDH2(2) allele.

Alcoholism↗
PubMed1996

The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion.

Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles. This allele encodes a protein subunit with a lysine for glutamate substitution at position 487 and is dominant over the wild-type allele, ALDH2*1. The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E). In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples. The half-lives of ALDH2 protein in HeLa cell lines expressing ALDH2*1, ALDH2*2, or both were determined by the rate of loss of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments. By either measure, ALDH2E enzyme was very stable, with a half-life of at least 22 h. ALDH2K enzyme had an enzyme half-life of only 14 h. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 h. Thus, the effect of ALDH2K on enzyme turnover is dominant. These studies indicate that the ALDH2*2 allele exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochondrial enzyme's turnover.

Aldehyde Dehydrogenase↗
PubMed2005

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

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed1999

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

BACKGROUND: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. METHODS: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. RESULTS: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. CONCLUSIONS: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.

Adolescent↗
PubMed1983

Determination of genotypes of human aldehyde dehydrogenase ALDH2 locus.

Virtually all Caucasians have two major aldehyde dehydrogenase isozymes, ALDH1 and ALDH2, in their livers, while approximately 50% of Japanese and other Orientals are "atypical" in that they have only ALDH1 and are missing ALDH2. We previously demonstrated the existence of an enzymatically inactive but immunologically cross-reactive material (CRM) in atypical Japanese livers. Among 10 Japanese livers examined, five had ALDH1 but not ALDH2 isozyme. These are considered to be homozygous atypical at the ALDH2 locus. Four had both ALDH1 and ALDH2 components detected by starch gel electrophoresis, that is, they are apparently usual. However, biochemical and immunological studies revealed that three of these four livers contained CRM. These three livers should be heterozygous atypical in the ALDH2 locus, that is, genotype ALDH2(1)/ALDH2(2). A Japanese liver, as well as control Caucasian livers, had no CRM, and they must be homozygous usual ALDH2(1)/ALDH2(1). Although the number of liver specimens examined is limited, the frequencies of three genotypes determined in this study are compatible with the values calculated based on the genetic model that two common alleles ALDH2(1) and ALDH2(2) for the same locus are codominantly expressed in Orientals. The remaining liver had only ALDH2 isozyme and was missing ALDH1. This type was not previously found in Caucasians and Orientals. The two-dimensional crossed immunoelectrophoresis revealed the existence of a CRM corresponding to ALDH1 in this liver. The abnormality can be considered to be due to structural mutation at the ALDH1 locus producing a defective ALDH1 molecule, although other possibilities such as post-translational modifications are not ruled out.

Aldehyde Dehydrogenase↗
PubMed2006

ALDH2 genotype-associated differences in the acute effects of alcohol on P300, psychomotor performance, and subjective response in healthy young Korean men: a double-blind placebo-controlled crossover study.

BACKGROUND: This study investigated the acute effects of alcohol on neurophysiological and psychomotor functions and the subjective response in healthy young Korean men according to the mitochondrial aldehyde dehydrogenase (ALDH2) genotype. METHOD: A total of 24 males, half with ALDH2*1/*1 (active form) and the rest with ALDH2*1/*2 (inactive form), were selected through genotyping. In a double-blind placebo-controlled crossover design, each subject consumed either a 0.5 g/kg dose of alcohol or a placebo on two separate occasions, 1 week apart. The blood alcohol concentrations (BACs), P300 of event-related potential, psychomotor performance, and perceived feelings were assessed. RESULTS: Although the BACs were similar between the two groups, the effects of alcohol on P300 were greater overall in subjects with ALDH2*1/*2 than in subjects with ALDH2*1/*1. Psychomotor performance was more impaired after alcohol ingestion in subjects with ALDH2*1/*2 than in subjects with ALDH2*1/*1. The subjective response after alcohol ingestion was more negative in subjects with ALDH2*1/*2, compared to subjects with ALDH2*1/*1. CONCLUSIONS: These results suggest that the ALDH2 polymorphism is an important factor in determining the effects of alcohol on various psychobehavioral functions.

Adult↗
PubMed2005

Expression levels of hepatic cytochrome P450 enzymes in Aldh2-deficient mice following ethanol exposure: a pilot study.

We determined expression levels of hepatic cytochrome P450 (CYP) 2E1, 2B1/2 and 4B1 enzymes in aldehyde dehydrogenase 2 (Aldh2) +/+ and Aldh2 -/- mice by immunoblotting assay following subchronic ethanol exposure for eight days. Using ethanol exposure, the protein expression levels of CYP2E1, 2B1/2 and 4B1 in Aldh2 +/+ mice were increased by factors of 2.61, 1.88 and 2.01 compared with Aldh2 +/+ mice that were not exposed to ethanol, respectively. On the other hand, in the Aldh2 -/- mice, CYP2E1, 2B1/2 and 4B1 protein expression levels after ethanol treatment were shown to be 1.99, 1.05 and 1.33 greater than those of Aldh2 -/- control mice, respectively. We also found an interesting fact in the present study; the Aldh2 -/- mice were shown to have higher CYP2E1 (by a factor of 4.19), 2B1/2 (by a factor of 2.89) and 4B1 (by a factor of 1.53) protein expression levels than Aldh2 +/+ mice despite the lack of ethanol treatment. These results suggest that CYP2E1, 2B1/2 and 4B1 play some role in ethanol metabolism and that Aldh2-deficient individuals may have higher levels of CYP2E1, 2B1/2 and 4B1 enzymes compared to Aldh2 wild-type individuals.

Aldehyde Oxidoreductases↗
PubMed2001

Effect of ALDH2 and CYP2E1 gene polymorphisms on drinking behavior and alcoholic liver disease in Japanese male workers.

AIMS: We examined the relationships of ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease in Japanese male workers. METHODS: Two hundred and eighty-seven Japanese men were selected from one metal company to adjust for similar economic and social backgrounds. Drinking behavior was assessed from a self-assessment questionnaire. Genotypes of ALDH2 and CYP2E1 were analyzed with the polymerase chain reaction-single strand conformation polymorphism and with the polymerase chain reaction-restriction fragment length polymorphism, respectively. RESULTS: The frequency of the ALDH2 genotype was 55% for typical homozygotes, 42% for heterozygotes, and 4% for atypical homozygotes. The frequency of the CYP2E1 genotype was 62% for c1 homozygotes, 35% for heterozygotes, and 3% for c2 homozygotes. The ALDH2 genotype closely influenced drinking habits, but not the CYP2E1 genotype. Among habitual drinkers, ALDH2 typical homozygotes consumed significantly larger amounts of ethanol than ALDH2 heterozygotes, whereas CYP2E1 genotypes did not influence daily alcohol consumption. Sixteen men (5.6%) were diagnosed with alcoholic liver disease. In terms of ALDH2 genotypes, 12 cases (7.6%) were typical homozygotes and 4 (3.4%) were heterozygotes, whereas the incidence of alcoholic liver disease was not different between c1/c1 homozygotes and c1/c2 heterozygotes. When the interactive contribution of the ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease were examined, there were no significant differences in the CYP2E1 genotype among the subjects with the same ALDH2 genotype. CONCLUSION: The ALDH2 genotype is strongly associated with individual alcohol drinking behavior and the development of alcoholic liver disease in Japanese male workers, but the CYP2E1 genotype is not.

Adult↗
PubMed2000

Accumulation of hemoglobin-associated acetaldehyde with habitual alcohol drinking in the atypical ALDH2 genotype.

BACKGROUND: Those with the atypical genotypes of low Km aldehyde dehydrogenase (ALDH2) have high blood concentrations of free acetaldehyde, an active metabolite of ethanol, after drinking alcohol. In the present study, we measured acetaldehyde reversibly bound to hemoglobin (HbAA) in Japanese male workers. METHODS: One hundred and sixty Japanese male workers in one plant participated with informed consent. The subjects were genotyped for the ALDH2 polymorphism by polymerase chain reaction method. HbAA levels were measured using a high performance liquid chromatography system with a fluorescence detector. For the study in which we examined accumulation of HbAA, eight Asian male volunteers participated with informed consent. RESULTS: Although HbAA levels were significantly correlated with recent alcohol consumption in both typical (ALDH2*1/*1) and atypical (ALDH2*1/*2) genotypes, the slope in ALDH2*1/*2 was significantly steeper than that in ALDH2*1/*1. Multiple regression analysis on relevant factors for HbAA revealed that not only recent but also daily alcohol consumption increased HbAA levels in those with the ALDH2*1/*2 genotype, which suggests that HbAA accumulates with habitual drinking. We measured HbAA levels before, during, and after alcohol consumption--one drink (0.4 ml/kg) per day--for 7 consecutive days in male volunteers. During the drinking period, HbAA linearly increased in ALDH2*1/*2 (n = 4) but not in ALDH2*1/*1 (n = 4). After reaching peak levels (+76.1 nmol/g hemoglobin) following the seventh drink, HbAA levels gradually decreased but were significantly higher for 3 days after drinking was discontinued. CONCLUSIONS: We demonstrated that HbAA levels accumulate with habitual alcohol drinking in the atypical ALDH2 genotype. HbAA was shown to be a good biomarker for increased internal exposure levels to acetaldehyde.

Acetaldehyde↗
PubMed1993

Dominance of the mutant ALDH2(2) allele in the expression of human stomach aldehyde dehydrogenase-2 activity.

About half of Chinese individuals lack mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity, which is responsible for the oxidation of acetaldehyde produced during ethanol metabolism. The ALDH2 deficiency in Chinese has been implicated in alcohol flush reaction and reported to be a negative risk factor for development of alcohol dependence. To assess the effects of inactive ALDH2 subunits, encoded by the mutant ALDH2(2) allele, on the catalytic activity of tetrameric enzyme molecules, we have phenotyped ALDH2 from 30 gastroendoscopic biopsies by using agarose isoelectric focusing and determined the genotypes from leukocytes of the same individuals by using polymerase-chain-reaction amplification and hybridization with allele-specific oligonucleotide probes. Sixteen subjects were homozygous for the ALDH2(1) allele, one was homozygous for ALDH2(2), and thirteen were the heterozygous genotype. None of the subjects with the mutant homozygotic and the heterozygotic genotypes exhibited the ALDH2 activity band or intermediate bands between ALDH2 and ALDH1 on isoelectric focusing gels. Our results support the notion that the mutant allele is dominant and that the heterotetrameric ALDH2 molecules containing the mutant subunits are enzymatically inactive or far less active.

Aldehyde Dehydrogenase↗
PubMed1995

Effects of ALDH2, CYP1A1, and CYP2E1 genetic polymorphisms and smoking and drinking habits on toluene metabolism in humans.

In this study, we evaluated the effects of ALDH2, CYP1A1, and CYP2E1 genetic polymorphisms and smoking and drinking habits on the toluene metabolism. The study subjects were 92 male workers who handle toluene in a printing factory, an electrical parts factory, and a painting workplace in Japan. Their exposure levels to toluene were monitored using the diffusion-type sampler. Benzyl alcohol concentrations in their blood and hippuric acid (HA) and creatinine concentrations in their urine at the end of a workshift were determined. The genotype of ALDH2 was classified into the homozygous genotype of a normal ALDH2 gene (NN), the homozygous genotype of an inactive ALDH2 gene (DD), and the heterozygous genotype of normal and inactive ALDH2 genes (ND). The genetic polymorphism of CYP1A1 and CYP2E1 were also determined by restriction fragment length polymorphism (RFLP). A strong correlation between the personal exposure level and the urinary HA concentration was observed. Regression lines were calculated after being divided by the five factors, i.e., ALDH2, CYP1A1, CYP2E1, smoking, and drinking. The HA formation from toluene was significantly (p < 0.001) different among the genotypes of ALDH2. The slopes of the regression lines decreased from NN to ND to DD in this order. The benzyl alcohol concentration in the blood of the DD group was significantly higher than that found in the NN and ND groups. This result demonstrates that ALDH2 polymorphism affects the oxidation of benzyl alcohol to benzoic acid. The toluene metabolism was also affected by CYP1A1 polymorphism. The slope for the Ile/Ile (the predominant homozygous allele) group was significantly lower than that for the Ile/Val (the heterozygous allele) and Val/Val (the rare homozygous allele) group after correction for creatinine. A drinking habit significantly (p < 0.05) reduced urinary HA concentration in the NN group. A smoking habit also significantly (p < 0.05) reduced urinary uncorrected HA concentration in both the NN and ND groups. In a multiple regression analysis, ALDH2 and the drinking habit were significantly (p < 0.01) associated with HA excretion after toluene exposure with and without correction for creatinine, and the corrected HA concentration was also significantly (p < 0.01) increased in the Ile/Val and Val/Val group of CYP1A1. The smoking habit reduced the corrected HA concentration (p < 0.05); however, the polymorphism in the 5'-flanking region of CYP2E1 did not affect HA appearance in urine.

Adult↗
PubMedDate not supplied

Apparent monomorphism of ALDH2 in seven American Indian populations.

Deficiency of mitochondrial aldehyde dehydrogenase (ALDH2) has been previously reported in South American Indians. We therefore assayed five individuals from each of five South American Indian populations (Quechua, Karitiana, Ticuna, Surui, Guahiba), and two North American populations (Maya and Moskoke) for the presence of the Oriental ALDH2(2) variant. These samples were also surveyed for other alleles altering ALDH2 function. Allele-specific amplification assay (ASA) did not detect the ALDH2(2) allele in any of the New World populations studied. The entire coding sequence of the ALDH2 cDNA was enzymatically amplified in partially overlapping fragments. Each fragment was digested using restriction endonucleases and subfragments 148-285 b.p. in length were analyzed by the single-stranded conformation polymorphism (SSCP) technique. No variants were detected within the coding region of the ALDH2 gene in any of the seven American Indian populations. Three potentially correct explanations for these results are suggested. First, an ALDH2 polymorphism is present but undetectable by SSCP; second, none of the studied individuals were ALDH2 negative; third, the polymorphism occurs beyond the coding region of ALDH2 gene.

Aldehyde Dehydrogenase↗
PubMed2000

Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse.

A principal pathway of 2-methoxyethanol (ME) metabolism is to the toxic oxidative product, methoxyacetaldehyde (MALD). To assess the role of aldehyde dehydrogenase (ALDH) in MALD metabolism, in vitro MALD oxidation was examined with liver subcellular fractions from Japanese subjects who carried three different ALDH2 genotypes and Aldh2 knockout mice, which were generated in this study. The activity was distributed in mitochondrial fractions of ALDH2*1/*1 and wild type (Aldh2+/+) mice but not ALDH2*1/*2, *2/*2 subjects or Aldh2 homozygous mutant (Aldh2-/-) mice. These data suggest that ALDH2 is a key enzyme for MALD oxidation and ME susceptibility may be influenced by the ALDH2 genotype.

Acetaldehyde↗
PubMed2003

Effects of ALDH2 gene polymorphisms and alcohol-drinking behavior on micronuclei frequency in non-smokers.

Alcohol abuse is a serious health problem, leading to life-threatening damage to most of the important organ systems. Genotoxic damage is used as an early effect indicator in the surveillance of human exposure to genotoxic substances. Intra- and inter-individual variations of baseline frequencies of micronuclei (MN) in peripheral blood lymphocytes of human populations have been reported previously. Polymorphisms in a few metabolic enzyme genes seem to account for a proportion of this variability, but the impact of specific genetic variants on MN frequencies has not yet been clarified. In 42 healthy Japanese non-smoking men, we investigated the relationship between the MN frequency levels and genetic polymorphisms in three different genes: aldehyde dehydrogenase 2 (ALDH2), X-ray repair cross-complementing group 1 (XRCC1) and excision repair cross-complementing group 2 (ERCC2). Genotyping was performed by PCR-RFLP analysis. The ALDH2 variant (deficient-type) was significantly associated with increased MN frequency levels in subjects with drinking more than three times per week, whereas the XRCC1 and ERCC2 variants seemed to be unrelated to the MN frequency. The ALDH2-deficient habitual drinkers had an average MN frequency of 5.88+/-0.58 (+/- S.E.) compared with 3.20 +/- 0.80 in the ALDH2-proficient habitual drinkers (P<0.05). The ALDH2-proficient non-habitual drinkers had the lowest MN frequency (1.56 +/- 0.41). Furthermore, subjects with highest levels of mean MN frequency, who consumed more than 100g of alcohol per week and more than three times per week, had A2 genotype of ALDH2. A significant odds ratio (12.25, P<0.05) for the MN frequency levels above the 50th percentile value was observed for the ALDH2-deficient individuals versus the ALDH2-proficient individuals after adjustment for several confounders. These results strongly suggest that human early genotoxic effect studies based on the cytogenetic markers of MN should take into account both the individual ALDH2 polymorphism and the potential confounding effect of the drinking behavior.

Adult↗
PubMed2001

Gene-environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer.

Aldehyde dehydrogenase-2 (ALDH2) degrades acetaldehyde metabolized from ethanol. Its encoding gene ALDH2 has a functional polymorphism: ALDH2 Glu487LYS: An association between this polymorphism and esophageal cancer among alcoholics has been reported. To further evaluate the gene-environment interaction, a hospital-based case-control study was conducted. Cases were 102 patients with histologically confirmed esophageal cancer and controls were 241 non-cancer outpatients of Aichi Cancer Center. ALDH2 genotypes were examined by a PCR-CTPP method developed in our laboratory, which does not require a digestion stage. Logistic regression analysis was employed for estimation of relative risk and gene-environment interaction. The allele frequency for ALDH2 Lys487 was 0.28, consistent with previous reports. The age, sex, smoking and drinking status adjusted odds ratio for the ALDH2 Glu/Lys and Lys/Lys genotypes as compared with the Glu/Glu genotype was 3.43 (95% CI 1.74-6.75). The odds ratio for heavy drinking was 49.6 (14.5-169.4) among Lys487 carriers and 7.84 (2.77-22.2) for the Glu/Glu genotype. The gene-environment interaction between alcohol drinking and the ALDH2 Lys487 allele was 6.84 (2.39-19.6), whereas no significant interaction was obtained with smoking status. Although limited because of its prevalent case-control design, our study revealed a strong gene-environment interaction between ALDH2 polymorphism and heavy alcohol consumption. Taking the observed high risk of esophageal cancer in association with the ALDH2 Lys487 allele into consideration, reducing alcohol intake may be most protective among Lys487 allele carriers of this polymorphism.

Adult↗
PubMed2005

A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan.

Alcohol consumption is recognized as a potential risk factor for colorectal cancer (CRC). Genetic polymorphisms, aldehyde dehydrogenase (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in Japanese population but their significance for CRC carcinogenesis remains to be clarified in detail. We, therefore, conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at Aichi Cancer Center, including analysis of interactions between polymorphisms, drinking and folate consumption. The ADH2 Arg allele was found to be associated with increased risk, the odds ratios (ORs) being 1.35 (95% confidence interval: 1.00-1.84) and 1.93 (1.06-3.53) for the His/Arg and Arg/Arg genotypes, respectively. In contrast, no apparent links were observed with the ALDH2 genotypes. Individuals having ALDH2 Glu/Glu with ADH2 Arg+, ALDH2 Lys+ with ADH2 His/His and ALDH2 Lys+ with ADH2 Arg+ showed ORs of 0.10(0.04-0.21), 0.10 (0.06-0.19) and 1.36 (0.94-1.97), respectively, compared with ALDH2 Glu/Glu with ADH2 His/His. Statistical gene-gene interaction was significant between the two polymorphisms for the risk of CRC (P< 0.001). The impact of ALDH2 Lys+ with ADH2 Arg+ was more evident in low folate consumer (OR = 2.32, 1.19-4.55) than high folate consumer (OR 1.38, 0.80-2.38). In conclusion, while we failed to find any significant association with the ALDH2 polymorphism itself, significant interaction between ALDH2 and ADH2 polymorphism was observed. Replication in the future study is warranted.

Adult↗
PubMed2003

Mutations in mitochondrial aldehyde dehydrogenase (ALDH2) change cofactor affinity and segregate with voluntary alcohol consumption in rats.

Genetic factors influence alcohol consumption and alcoholism. A number of groups have bred alcohol drinker and non drinker rat strains, but genetic determinants remain unknown. The University of Chile rat lines UChA (low drinkers) and UChB (high drinkers) display differences in the relative K(m) for NAD+ of mitochondrial aldehyde dehydrogenase (ALDH2) but no V(max) differences. The relative K(m) differences may be due to mitochondrial changes or to genetic differences coding for ALDH2. We investigated whether there are differences in the coding regions of ALDH2 cDNA in these lines and whether the Aldh2 genotype predicts the phenotype of alcohol consumption and the K(m) of ALDH2 for NAD+. Liver cDNA was prepared, and the Aldh2 transcript was amplified, cloned and sequenced. Genotyping was conducted by DNA amplification and restriction enzyme digestion. When compared to Aldh21 of Sprague-Dawley, 94% of the UChA (low drinker) rats (n = 61), presented a mutation that changes Gln67 to Arg in the mature enzyme (allele referred to as Aldh22). In UChB (high drinker) rats (n = 69), 58% presented the Aldh21 allele, while 42% presented the Gln67Arg change plus a second mutation that changed Glu479 to Lys (allele Aldh23). The Aldh22 allele was absent in high drinker rats. Rats of different Aldh2 genotypes displayed marked phenotypic differences in both ethanol consumption (g/kg/day; means +/- SE): (Aldh21/Aldh21) = 5.7 +/- 0.2, (Aldh22/Aldh22) = 0.9 +/- 0.2 and (Aldh23/Aldh23) = 4.6 +/- 0.2; and K(m)s for NAD+ of 43 +/- 3 microm, 132 +/- 13 microm and 41 +/- 2 microm, respectively (Aldh22 versus Aldh21 or Aldh23; P < 0.0001 for both phenotypes). Overall, the data show that alleles of Aldh2 strongly segregate with the phenotype of ethanol consumption and the relative K(m) for NAD+ of ALDH2. Bases mutated suggest that non drinker Aldh22 is ancestral with regard to the coding changes in either Aldh21 or Aldh23, variants which would allow ethanol consumption and may provide an evolutionary advantage by promoting calorie intake from fermented products along with carbohydrates.

Aldehyde Dehydrogenase↗
PubMed2005

Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism.

In alcohol metabolism, acetaldehyde, a highly reactive intermediate that may cause cellular and DNA damages, is converted to acetate by mitochondrial aldehyde dehydrogenase ALDH2. Although the majority of ingested alcohol is eliminated in the liver, the first-pass metabolism of ethanol in the upper digestive tract is also important for prevention and management of ethanol-related gastrointestinal diseases. However, the tissue-distribution of Aldh2 in mice has been poorly investigated. In this study, therefore, we investigated the tissue-distribution of Aldh2 as well as Aldh1, Cyp1a1, Cyp2e1, and Cyp4b1 in wild type and Aldh2-null mice by immuno-histochemical analysis. The human liver and esophageal tissues were also examined. In mice, the Aldh2 protein was detected in the liver, lung, heart, kidney, testis, esophagus, stomach, colon, and pancreas, suggesting that the tissue-distribution of Aldh2 in mice is similar to that in humans. Therefore, Aldh2-null mice may be useful model animals for the investigation of alcohol metabolism and related diseases. Compared with the wild type, the expression level of Cyp2e1 was increased in the liver from Aldh2-null mice based on Western blot analysis, whereas the levels of Aldh1, Cyp1a1, and Cyp4b1 were indistinguishable. This observation suggests that a metabolite(s) of Aldh2 might down-regulate the expression of Cyp2e1 gene.

Alcohols↗