Aldehyde Dehydrogenase 2 Polymorphism Research Articles

Correlations between polymorphisms of extracellular superoxide dismutase, aldehyde dehydrogenase-2 genes, as well as drinking behavior and pancreatic cancer.

To investigate the correlation between drinking behavior combined with polymorphisms of extracellular superoxide dismutase (EC-SOD) and aldehyde dehydrogenase-2 (ALDH2) genes and pancreatic cancer. The genetic polymorphisms of EC-SOD and ALDH2 were analyzed by polymerase chain reaction restriction fragment length polymorphism in the peripheral blood leukocytes obtained from 680 pancreatic cancer cases and 680 non-cancer controls. Subsequently the frequency of genotype was compared between the pancreatic cancer patients and the healthy controls.The relationship of drinking with pancreatic cancer was analyzed. The frequencies of EC-SOD (C/G) and ALDH2 variant genotypes were 37.35% and 68.82% respectively in the pancreatic cancer cases, and were significantly higher than those in the healthy controls (21.03% and 44.56%, all P<0.01). People who carried EC-SOD (C/G) (OR=2.24, 95% CI= 1.81-4.03, P<0.01) or ALDH2 variant genotypes (OR=2.75, 95% CI=1.92-4.47, P<0.01) had a high risk to develop pancreatic cancer. Those who carried EC-SOD (C/G) genotype combined with ALDH2 variant genotype had a high risk for pancreatic cancer (29.56% vs. 6.76%, OR=7.69, 95% CI=3.58-10.51, P<0.01). The drinking rate of the pancreatic cancer group (64.12%) was significantly higher than that of the control group (40.15%; OR=2.66, 95% CI=1.30-4.42, P<0.01). An interaction between drinking and EC-SOD (C/G)/ALDH2 variant genotypes increased the risk of occurrence of pancreatic cancer (OR=25.00, 95% CI= 11.87-35.64, P<0.01). EC-SOD (C/G), ALDH2 variant genotypes and drinking might be the risk factors of pancreatic cancer.

Role ofDRD2andALDH2genes in bipolar II disorder with and without comorbid anxiety disorder

The presence of comorbid anxiety disorders (AD) and bipolar II disorders (BP-II) compounds disability complicates treatment, worsens prognosis, and has been understudied. The genes involved in metabolizing dopamine and encoding dopamine receptors, such as aldehyde dehydrogenase 2 (ALDH2) and dopamine D2 receptor (DRD2) genes, may be important to the pathogenesis of BP-II comorbid with AD. We aimed to clarify ALDH2 and DRD2 genes for predisposition to BP-II comorbid with and without AD. The sample consisted of 335 subjects BP-II without AD, 127 subjects BP-II with AD and 348 healthy subjects as normal control. The genotypes of the ALDH2 and DRD2 Taq-IA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a statistically significant association between DRD2 Taq-I A1/A2 genotype and BP-II with AD (OR=2.231, P=0.021). Moreover, a significant interaction of the DRD2 Taq-I A1/A1 and the ALDH2*1*1 genotypes in BP-II without AD was revealed (OR=5.623, P=0.001) compared with normal control. Our findings support the hypothesis that a unique genetic distinction between BP-II with and without AD, and suggest a novel association between DRD2 Taq-I A1/A2 genotype and BP-II with AD. Our study also provides further evidence that the ALDH2 and DRD2 genes interact in BP-II, particularly BP-II without AD.

The Glu504Lys polymorphism of aldehyde dehydrogenase 2 contributes to development of coronary artery disease.

Coronary artery disease (CAD) is a leading cause of death, and its genetic mechanism has been always a major research concern. Recently, increasing evidence has indicated that the aldehyde dehydrogenase 2 (ALDH2) polymorphism, known as Glu504Lys (rs671), may contribute to CAD development. ALDH2 has been well known as a key enzyme in alcohol metabolism, and subjects with *504Lys allele exist in 30-50% of the East Asian population (6% of the world's population). However, recent studies have indicated that the *504Lys allele of the ALDH2 gene may be associated with the pathogenesis of CAD in a given number of Chinese, Japanese, and Korean people. This discovery has been further confirmed by a genome-wide association study in 2012 that identified the link of ALDH2 Glu504Lys polymorphism to CAD susceptibility. ALDH2 may therefore serve as an important target for CAD intervention. Several studies have suggested that ALDH2 polymorphism plays an important role in the progress of CAD through multiple mechanisms, including the regulation of alcohol consumption, inflammation, endothelial progenitor cells, oxidative stress, asymmetric dimethylarginine, endothelial nitric oxide synthase, and other CAD-promoting factors. Furthermore, the ALDH2 Glu504Lys polymorphism has been shown to be associated with certain traditional cardiovascular risk factors, such as dyslipidemia, hypertension, and diabetes mellitus or hyperglycemia. In this review, we update the current research on the association of the Glu504Lys polymorphism with the susceptibility to CAD. We also highlight and discuss the underlying mechanisms, by which the ALDH2 Glu504Lys polymorphism may be targeted for the prevention and treatment of CAD.

Polymorphisms in the aldehyde dehydrogenase 2 and dopamine β hydroxylase genes are not associated with Alzheimer’s disease

Since ethanol and its metabolite, acetaldehyde, are directly neurotoxic, alcohol intake could affect the development of Alzheimer's disease (AD). Mitochondrial aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde into acetate and also protects against oxidative stress, playing an important role in the development of AD. The activity of dopamine β hydroxylase (DBH) is reduced in the hippocampus and neocortex in the AD brain. DBH is also involved in the pathophysiology of alcoholism. The aim of this study was to investigate whether polymorphisms of both ALDH2 and DBH genes were associated with AD. ALDH2*2 and two functional single nucleotide polymorphisms (SNPs) of the DBH gene were analyzed using a case-control study design. Our case-control data set consisted of 201 AD patients and 130 age-matched controls. We also analyzed stratifying by alcohol consumption and apolipoprotein E (APOE) genotypes. There were no associations between the SNPs studied here and the onset of AD. No synergetic associations were found among the SNPs, APOE and the risk for AD. Although high alcohol consumption AD (HAC-AD) patients were analyzed in detail, the current three SNPs were not related with HAC-AD. ALDH2*2 and functional SNPs of the DBH gene did not modify the risk for AD. Since our data set was constructed only with AD in a Japanese population, further detailed genetic analyses with other ethnic groups would be needed.

Advances in cancer epidemiology in Japan

Epidemiologists in Japan have been performing calculations to estimate nationwide cancer incidence rates as well as 5-year survival rates using population-based cancer registry data. There have been remarkable changes in cancer incidence and/or mortality in cancers of the lung, liver and stomach, which were thought to be attributed to the changing impact of exposure to cigarette smoking, chronic hepatitis C virus infection and Helicobacter pylori infection, respectively. In systematic reviews providing evidence in risk/protective factors for cancer sites using case-control and cohort studies of the Japanese population, there were associations between cancer sites (esophagus, stomach, colo-rectum, liver, pancreas, lung and breast) and various lifestyle factors. In the past 10 years, a hospital-based case-control study at Aichi Cancer Center provided valuable evidence of gene-environment interaction on the development of cancer [i.e., the effects of aldehyde dehydrogenase-2 (ALDH2) polymorphism and heavy alcohol drinking on esophageal cancer, ALDH2 polymorphism and smoking on lung cancer, methylenetetrahydrofolate reductase polymorphism and heavy alcohol drinking on pancreatic cancer]. The database with stored DNA was also used and identified seven loci containing significant but low-penetrance polymorphisms associated with the development of breast cancer. These findings together with established risk factors are likely to be useful to predict personalized breast cancer risk in East Asian women. In 2005, the Japan Multi-Institution Collaborative Cohort (J-MICC) study was launched to elucidate gene-environment interactions as well as to confirm preclinical diagnostic biomarkers of cancer. J-MICC, which has recruited 92,000 healthy individuals by the end of 2012, will follow the individuals until 2025.

Sulforaphane Accelerates Acetaldehyde Metabolism by Inducing Aldehyde Dehydrogenases: Relevance to Ethanol Intolerance

Many East Asians are highly intolerant to even modest alcohol consumption. These individuals accumulate acetaldehyde, the primary metabolite of ethanol, because of a genetic polymorphism of aldehyde dehydrogenase (ALDH) that metabolizes acetaldehyde to nontoxic acetate. The aim of these studies is to upregulate ALDH by dietary means, thereby reducing acetaldehyde toxicity. Sulforaphane [SF, 1-isothiocyano-4-(methylsulfinyl)butane] derived from its glucosinolate precursor contained in cruciferous vegetables and related inducers of the Keap1/Nrf2/ARE pathway were assessed for their potencies to induce ALDH in murine hepatoma Hepa1c1c7 cells. Inducer potencies for ALDH were compared with those for NQO1, a prototypical cytoprotective enzyme present downstream of the Keap1/Nrf2/ARE pathway. SF (5 or 20 µmol/day) was fed to CD-1 mice for 7 days prior to a single administration of ethanol, and then ALDH induction in organs and pharmacokinetics of acetaldehyde was examined. In addition to SF, other electrophiles, including many Michael reaction acceptors, induce ALDH. Potencies of these agents as inducers parallel their activities in inducing NQO1, and are also dependent on Nrf2. In mice, in vivo, feeding of SF induced tissue ALDH and dramatically increased (doubled) the rate of elimination of acetaldehyde arising from the administration of ethanol. SF and other edible phytochemicals may ameliorate the alcohol intolerance of individuals who are polymorphic with respect to ALDH.

OP228: Elucidating risk factors for oral leukoplakia affecting gingivae among a Japanese population

Purpose Population screening studies in Japanese have confirmed that oral leukoplakia (OL) affecting the gingivae (gingival leukoplakia: GL) is the most frequent location of OL. We investigated a cohort of patients with GL and their clinic-pathological features were compared with patients with OL affecting other sites (n-GL). Methods Among 204 subjects diagnosed with OL (GL:114, n-GL:90) during 09-11 in 4 city hospitals in Japan, 151(74%) subjects (GL:88, n-GL:63) (age: 64.4 ± 12.7) were recruited. OL was diagnosed by WHO criteria (Warnakulasuriya et al., J Oral Pathol Med, 2007). They were interviewed for risk factors and investigated by patch testing for dental materials, biopsy for dysplasia recording and detection of aldehyde dehydrogenase (ALDH2) polymorphism in saliva by Real-Time PCR for SNP genotyping (rs671) and screened for HPV-DNA by GP5+/6+PCR from paraffin-embedded tissues among selected subjects ( n = 31). Results There were no significant differences by age (mean ages: GL, 65.9; n-GL, 62.3) or in tobacco and alcohol use in the two groups. Eighty-one percent of GL were seen in association with prosthesis and 27% close to amalgam fillings. Metal allergy test was positive in 58% of the GL but was not significantly higher compared to the n-GL (41%). Higher dysplasia grades were found in n-GL ( P = 0.018). Alcohol intolerance (flush reaction) was higher in n-GL (73%) ( P = 0.035). The homozygous ALDH2∗2/2 and 2∗1/2, which work less efficiently in alcohol metabolism was higher in n-GL (55%) than in GL (41%). HPV-DNA was not detected in any of the samples. Conclusions GL had lower dysplasia scores compared to n-GL, but the risk factors appear similar. Oral leukoplakia in n-GL may be associated with aberrant oxidative pathway of alcohol metabolism in Japanese. There was no evidence to support a causal relationship between HPV-DNA detection and GL nor n-GL (Funded by Sasakawa GB Foundation).

Meta-analysis of the ADH1B and ALDH2 Polymorphisms and the Risk of Colorectal Cancer in East Asians

The aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) genes have been implicated in the development of colorectal cancer (CRC). However, the results are inconsistent. In this study, a meta-analysis was performed to assess the associations between the ALDH2 and ADH1B polymorphisms and the risk of CRC. Relevant studies were identified using PubMed, Web of Science and CNKI up to February, 2013. The pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated using the fixed- or random-effects model. A total of 11 case-controlled studies were selected. Of these, 11 studies included 2,893 cases and 3,817 controls concerning the ALDH2 Glu487Lys polymorphism and six studies included 1,864 cases and 3,502 controls concerning the ADH1B polymorphism. The results indicated that there was a statistically significant link between the ALDH2 polymorphism and the risk of CRC (Glu/Lys+Lys/Lys vs. Glu/Glu: OR=0.87, 95%CI: 0.78-0.96, p=0.10; Glu/Lys vs. Glu/Glu: OR=0.87, 95%CI: 0.77-0.97, p=0.38); however, no significant associations were observed between the ADH1B polymorphism and the risk of CRC win any of the genetic models. This meta-analysis demonstrated that the ALDH2 polymorphism, but not the ADH1B polymorphism, significantly increases the risk of CRC in East Asians.

Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The current study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor allele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results support the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.

The ADH1B and DRD2 gene polymorphism may modify the protective effect of the ALDH2 gene against heroin dependence

Understanding the influences of genes involved in dopamine and serotonin metabolism, such as the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) genes, is critical for understanding addictive behavior. In addition, dopamine D2 receptor (DRD2) gene may also interact with the dopamine metabolizing genes and link to addiction. Therefore, we investigated the association between the ALDH2, ADH1B and DRD2 polymorphisms and heroin dependence. Heroin-dependent Han Chinese patients (n=304) and healthy controls (n=335) were recruited. Genotypes of ALDH2, ADH1B and DRD2 polymorphisms were analyzed using a polymerase chain reaction with restriction fragment length polymorphism. The frequency of the ALDH2*1/*1 genotype was significantly lower in heroin-dependent patients than in controls, but the frequency of ADH1B and DRD2 genotypes was not significantly different. Further stratification of the ALDH2 gene with the ADH1B gene showed that the protective effect of ALDH2*1/*1 existed only in patients who also carried the ADH1B*1/*1 and ADH1B*1/*2 genotype. Logistic regression analysis showed a significant interaction between ALDH2 and ADH1B (P=0.022) and DRD2, ALDH2 and ADH1B in patients (P=0.037). The ALDH2*1/*1, ADH1B*1/*1, and ADH1B*1/*2 genotypes may interact and protect their carriers against heroin dependence and the protective effect may be varied by the DRD2 gene polymorphism. We conclude that the protective effect of the ALDH2 polymorphism against heroin dependence may be modified by the ADH1B and DRD2 polymorphism.

Aldehyde dehydrogenases: From eye crystallins to metabolic disease and cancer stem cells

The aldehyde dehydrogenase (ALDH) superfamily is composed of nicotinamide adenine dinucleotide (phosphate) (NAD(P)+)-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. To date, 24 ALDH gene families have been identified in the eukaryotic genome. In addition to aldehyde metabolizing capacity, ALDHs have additional catalytic (e.g. esterase and reductase) and non-catalytic activities. The latter include functioning as structural elements in the eye (crystallins) and as binding molecules to endobiotics and xenobiotics. Mutations in human ALDH genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases. Most recently ALDH polymorphisms have been associated with gout and osteoporosis. Aldehyde dehydrogenase enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. This article serves as a comprehensive review of the current state of knowledge regarding the ALDH superfamily and the contribution of ALDHs to various physiological and pathophysiological processes.

ADH and ALDH Polymorphisms and Alcohol Dependence in Mexican and Native Americans

Background: Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. Objectives and methods: Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county. Results: Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. Conclusions and Scientific Significance: Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations.

Association of genetic polymorphisms of aldehyde dehydrogenase-2 and cytochrome P450 2E1-RsaI and alcohol consumption with oral squamous cell carcinoma.

To investigate the association of the polymorphisms of aldehyde dehydrogenase-2(ALDH2) and CYP2E1-RsaI genes and alcohol consumption with oral squamous cell carcinoma (OSCC). The genetic polymorphisms of ALDH2 and CYP2E1-RsaI were determined by polymorphism-polymerase chain reaction (PCR) technique in the peripheral blood leukocytes of 320 OSCC patients and 320 non-cancer controls. The frequencies of ALDH2 variant genotypes and CYP2E1-RsaI (c2/c2) were 70.94% and 39.06% in the OSCC group and 43.44% and 20.62% in the control group (both P<0.01). The risk of OSCC with ALDH2 variant genotypes was significantly higher than that in control group (OR=3.178, 95% CI=1.917-4.749), whereas the subjects carried with CYP2E1-RsaI (c2/c2) also had a high risk of OSCC (OR=2.467, 95%CI=1.783-4.045). Combined analysis of the polymorphisms showed that percentage of ALDH2 variant genotypes/CYP2E1-RsaI (c2/c2) in OSCC group and control group was 32.19% and 6.25%, respectively (P<0.01). Carriers of ALDH2 variant genotypes/CYP2E1-RsaI (c2/c2) had a high risk of OSCC (OR=9.792, 95%CI=3.583-12.472). The percentage of alcohol consumption was significantly higher in OSCC group than in the control group (OR=2.861, 95% CI=1.541-4.781, P<0.01), and ALDH2 variant genotypes and CYP2E1-RsaI (c2/c2) showed synergic effects with alcohol consumption for the increased risk of OSCC (OR=41.152, 95%CI=19.903-67.551). The polymorphisms of ALDH2 and CYP2E1-RsaI genes and alcohol consumption, independently and synergically, increase the risk of OSCC.

Developmental Trajectory and Environmental Moderation of the Effect of ALDH2 Polymorphism on Alcohol Use

In the aldehyde dehydrogenase 2 (ALDH2) gene, the ALDH2*2 allele, prevalent in East Asian populations, encodes an enzyme with severely reduced activity, thereby disrupting the normal metabolism of alcohol. Possession of the ALDH2*2 allele has been repeatedly shown to be associated with lower risk for alcohol dependence and reduced alcohol use. However, relatively few studies have considered whether the magnitude of the effect of ALDH2 polymorphism upon drinking is related to developmental stage or varies by environmental context. In a longitudinally assessed sample of 356 adopted adolescents and young adults of East Asian descent, we examined the progression over time of the relationship between ALDH2 genotype and multiple measures of drinking behavior. We also sought to determine whether the environmental influences of nonbiological parent and elder sibling alcohol use and misuse, as well as deviant peer behavior, moderated the effect of ALDH2 genotype upon alcohol use. Across all measures of alcohol use, the association between ALDH2*2 allele possession and reduced drinking went from negligible to moderate between mid-adolescence and early adulthood. A combined index of adoptive parent alcohol use and misuse consistently moderated the protective effect of the ALDH2*2 allele across the measures of quantity and frequency of alcohol use, and symptomology, such that high parental alcohol use and misuse reduced the protective effect of the ALDH2*2 allele, while low parental alcohol use and misuse enhanced the effect of the allele. Neither a combined index of elder sibling alcohol use and misuse, nor deviant peer behavior was consistently related to the effect of ALDH2 genotype. The protective effect of the ALDH2*2 allele increases over the course of adolescence and young adulthood and is modified by the environmental influence of parental alcohol use and misuse. As such, ALDH2 provides a model system for exploring the nature of gene-environment interplay across development.

The ALDH2 and 5-HT2A genes interacted in bipolar-I but not bipolar-II disorder

Clarifying the similarities and differences between the two most common subtypes of bipolar disorder, bipolar-I and bipolar-II, is essential for improving our understanding of them. Because the serotonergic system has been implicated in the pathogenesis of bipolar disorder, it may be important to investigate genes such as the aldehyde dehydrogenase 2 (ALDH2) and serotonin 2A receptor genes, which are involved in metabolizing serotonin and encoding serotonin receptors. We examined the association of the ALDH2 and 5-HT2A-A1438G polymorphisms with bipolar I and II and possible interactions between these genes. One thousand forty-nine participants were recruited: 249 with bipolar-I, 456 with bipolar-II, and 344 healthy controls. The genotypes of the ALDH2 and 5HT2A-A1438G polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the ALDH2 and the 5-HT2A-A1438G polymorphisms, and a significant interaction effect for the A/G genotypes of the 5-HT2A-A1438G polymorphism and the ALDH2*1*1 genotypes (p=0.004) discriminated between bipolar-I patients and controls without bipolar disorder. These polymorphisms, however, were not associated with bipolar-II disorder. The significant differences of age and gender between patients and controls limit the comparison, although statistical adjustments were made for them. Our findings provide initial evidence that the ALDH2 and 5-HT2A genes interact in bipolar-I but not in bipolar-II disorder. Our findings suggest a unique genetic distinction between bipolar-I and bipolar-II.

Effects and Action Mechanisms of Korean Pear (Pyrus pyrifolia cv. Shingo) on Alcohol Detoxification

Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2∼3- and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(∞) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol-metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification.

Folate, alcohol, and aldehyde dehydrogenase 2 polymorphism and the risk of oral and pharyngeal cancer in Japanese

Folate consumption is inversely associated with the risk of oral and pharyngeal cancer (OPC) and potentially interacts with alcohol drinking in the risk of OPC. Aldehyde dehydrogenase 2 (ALDH2) gene polymorphism is known to interact with alcohol consumption. The aim of this study was to investigate potential interaction between folate, alcohol drinking, and ALDH2 polymorphism in the risk of OPC in a Japanese population. The study group comprised 409 head and neck cancer cases and 1227 age-matched and sex-matched noncancer controls; of these, 251 cases and 759 controls were evaluated for ALDH rs671 polymorphism. Associations were assessed by odds ratios and 95% confidence intervals in multiple logistic regression models. We observed an inverse association between folate consumption and OPC risk. The odds ratio for high folate intake was 0.53 (95% confidence interval: 0.36-0.77) relative to low intake (P trend=0.003). This association was consistent across strata of sex, age, smoking, and ALDH2 genotypes. Interaction between folate consumption, drinking, and ALDH2 genotype was remarkable (three-way interaction, P<0.001). We observed significant interaction among folate, drinking, and ALDH2 genotype in the Japanese population.

Genetic polymorphisms of ALDH2 and ADH2 are not associated with risk of hepatocellular carcinoma among East Asians

The aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 2 (ADH2) genes have been implicated in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between polymorphisms of ALDH2 and ADH2 genes and HCC. Published literatures from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Ten studies including 1,231 HCC cases and 1,849 controls were included in the meta-analysis of the association between ALDH2 polymorphism and HCC risk. The results indicated that ALDH2 polymorphism was not significantly associated with risk of HCC (homogeneous co-dominant model: OR = 0.99, 95% CI 0.72-1.34; heterogeneous co-dominant model: OR = 0.90, 95% CI 0.75-1.08; dominant model: OR = 0.91, 95% CI 0.70-1.18; recessive model: OR = 1.11, 95% CI 0.66-1.87). In addition, four studies including 518 cases and 607 controls were included in the meta-analysis of the association between ADH2 polymorphism and HCC risk. There was no association between ADH2 polymorphism and HCC risk (homogeneous co-dominant model: OR = 0.93, 95% CI 0.58-1.51; heterogeneous co-dominant model: OR = 1.39, 95% CI 0.87-2.23; dominant model: OR = 1.19, 95% CI 0.76-1.88; recessive model: OR = 0.91, 95% CI 0.54-1.54). Further analysis suggested that the ALDH2 polymorphism-alcohol interaction was marginally associated with HCC risk under the dominant model (OR = 2.05, 95% CI 1.01-4.17). However, the result was not robust by sensitivity analysis. The results from the present meta-analysis indicated that there was no significant association between ALDH2 polymorphism, ADH2 polymorphism, or ALDH2 polymorphism-alcohol intake interaction and HCC risk in the East Asians.

Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice

Ethyl tertiary butyl ether (ETBE) is used as an additive to gasoline to reduce carbon monoxide emissions in some developed countries. So far, ETBE was not found with positive results in many genotoxic assays. This study is undertaken to investigate the modifying effects of deficiency of aldehyde dehydrogenase 2 (ALDH2) on the toxicity of ETBE in the livers of mice. Eight-week-old wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice of both sexes were exposed to 0, 500, 1,750, and 5,000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Histopathology assessments and measurements of genetic effects in the livers were performed. Significantly increased accidences of centrilobular hypertrophy were observed in the livers of WT and KO mice of both sexes in 5,000 ppm group; there was a sex difference in centrilobular hypertrophy between male and female KO mice, with more severe damage in the males. In addition, DNA strand breaks, 8-hydroxyguanine DNA-glycosylase (hOGG1)-modified oxidative base modification, and 8-hydroxydeoxyguanosine as genetic damage endpoints were significantly increased in three exposure groups in KO male mice, while these genotoxic effects were only found in 5,000 ppm group of KO female mice. In WT mice, significant DNA damage was seen in 5,000 ppm group of male mice, but not in females. Thus, sex differences in DNA damage were found not only in KO mice, but also in WT mice. These results suggest that ALDH2 polymorphisms and sex should be taken into considerations in predicting human health effects of ETBE exposure.

Role of aldehyde dehydrogenase 2 Glu504lys polymorphism in acute coronary syndrome

This study aimed to investigate the association of the aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism, which exists in 30–50% of East Asians, and risk of acute coronary syndrome (ACS). We enrolled 1092 unrelated Han Chinese, including 546 with ACS and 546 age- and sex-matched controls. Subjects with ALDH2 mutant genotypes showed significantly higher ACS than did controls (46.7% versus 31.9%, P < 0.001). Logistic regression analysis revealed the ALDH2 mutant independently associated with ACS (odds ratio [OR] 1.95, 95% confidence interval [CI]: 1.31–2.92, P = 0.001), but the association was weaker on adjusting for alcohol consumption (OR 1.82, 95% CI: 1.23–2.70, P = 0.003). Similar results were found in a subgroup analysis of patients with primary ST-segment elevation myocardial infarction (STEMI). The ALDH2 mutant was significantly associated with level of high-sensitivity C-reactive protein (hs-CRP) in patients with ACS (P = 0.002) and in controls (P = 0.009) and number of circulating endothelial progenitor cells (EPCs) (P = 0.032); furthermore, inclusion of hs-CRP level and EPCs number as independent variables in regression analysis reduced the importance of ALDH2 polymorphism in ACS or primary STEMI. However, ALDH2 polymorphism was not associated with number of coronary arteries with significant stenosis, Gensini score or flow-mediated dilation of the brachial artery. Our results suggest that ALDH2 mutation is a genetic risk marker for ACS, which is explained in part by alcohol consumption, inflammation and number of circulating EPCs.