ALDH2 Genotypes Research Articles

The Influence of Prediagnosis Alcohol Consumption and the Polymorphisms of Ethanol-Metabolizing Genes on the Survival of Head and Neck Cancer Patients.

Although alcohol drinking is an established risk factor of head and neck cancer (HNC), less is known about its role in the prognosis of HNC. The current study investigated the association between pretreatment alcohol consumption and the overall survival (OS) of HNC patients. Cox proportional hazards models were performed to evaluate the association between prediagnosis alcohol drinking and the OS of HNC patients. In addition, the influence of the polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on this relationship was also evaluated. The results showed a significant positive dose-response relationship between prediagnosis alcohol use and worse OS of HNC patients. This association was more significant for oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer than for oral cancer. The association between alcohol use and the poorer OS of HNC patients was mainly through its association with a higher stage of HNC at diagnosis. The worst OS associated with alcohol use was observed among HNC patients with the fast ADH1B and the slow/nonfunctional ALDH2 genotype combination. Our analysis showed a significant positive dose-response relationship between prediagnosis alcohol use and a worse OS of HNC. This association was mainly due to the higher stage of HNC among alcohol drinkers. In addition, the polymorphisms of the ethanol-metabolizing genes, ADH1B and ALDH2, modified the relationship between prediagnosis alcohol use and the OS of HNC patients. Prediagnosis alcohol use may be a prognostic indicator of HNC.

Endoscopic screening using esophageal iodine staining and genotypes of ADH1B and ALDH2 in Japanese alcohol-dependent women.

BackgroundThe presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field.MethodsUsing multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women.ResultsDIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio [95% confidence interval], 12.5 [4.82–32.4] and 9.89 [3.50–27.9]), the inactive heterozygous ALDH2*1/*2 genotype (2.94 [1.18–7.38] and 3.79 [1.40–10.3]), a lower body mass index per -1 kg/m2 (1.17 [1.02–1.35] and 1.38 [1.14–1.67]), and a mean corpuscular volume ≥106 fl (3.70 [1.56–8.81] and 3.27 [1.24–8.64]) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 [10.6–146]).ConclusionsJapanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.

Alcohol Intake Interacts with Functional Genetic Polymorphisms of Aldehyde Dehydrogenase (ALDH2) and Alcohol Dehydrogenase (ADH) to Increase Esophageal Squamous Cell Cancer Risk

IntroductionStudies have reported alcohol consumption and genetic variants as major contributing factors for esophageal squamous cell carcinoma (ESCC). However, the complicated interactions between alcohol and genetic factors involved in alcohol metabolism have not been well elucidated with respect to augmented risk of ESCC. MethodsWe performed a large population-based case-control study in a Chinese city with a high ESCC incidence by enrolling 1190 case patients and 1883 controls. We integrated candidate single-nucleotide polymorphism data, detailed alcohol consumption records, gene-alcohol interactions, and single-nucleotide polymorphism functional information to untangle the complicated relationship between alcohol, variants of genes encoding alcohol metabolism enzymes, and ESCC risk. The gene-alcohol interaction was tested by including their product term in a multivariable logistic regression model. Synergy index and ratio of ORs were calculated to assess interaction on additive and multiplicative scale, respectively. ResultsWe confirmed two ESCC susceptibility loci, rs671 in aldehyde dehydrogenase 2 family member gene (ALDH2) and rs1042026 in alcohol dehydrogenase 1B (class I), beta polypeptide gene (ADH1B), that significantly altered alcohol consumption behavior and subsequently modified the association between alcohol consumption and ESCC risk. The rs671(A) allele was associated with ESCC risk in alcohol drinkers (adjusted odds ratio =1.98, 95% confidence interval [CI]: 1.51–2.60) but not in nondrinkers. Healthy individuals who carry different ALDH2 and ADH1B genotypes exhibit diversified drinking behavior, with the proportion of drinkers varying between 23.7% and 54.3%. Among individuals with a fast ethanol oxidization rate, we observed a strong interaction between heavy alcohol consumption and ethanal oxidization rate on both the additive scale (synergy index 4.80 [95% CI: 1.82–12.68]) and the multiplicative scale (ratio of ORs 2.93, 95% CI: 1.39–6.35). ConclusionsOur observation highlights the need for preventing excessive use of alcohol, especially in individuals harboring active alcohol dehyrogenase and inactive ALDH2 variants.

Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde

Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress.

Differences in the genetic backgrounds of patients with alcoholic liver disease and non-alcoholic fatty liver disease.

Background and AimAlcoholic liver disease (ALD) and non‐alcoholic fatty liver disease (NAFLD) have common hepatic histological features, but few studies have compared the genomic backgrounds of these two diseases. Here, we compared the genetic differences between ALD and NAFLD.MethodsThis study enrolled 318 Japanese patients with ALD (n = 118; male, 86%; median age, 62 years; liver cirrhosis, 58%; hepatocellular carcinoma [HCC], 31%) and NAFLD (n = 200; male, 55%; age, 61 years; cirrhosis, 19%; HCC, 12%). The genotype frequencies of 10 single nucleotide polymorphisms (SNPs) were analyzed.ResultsThe ADH1B genotype GG and ALDH2 genotype GG were observed more frequently, and the percentage of patients with the MTP genotype GG was lower in ALD compared with NAFLD patients (ADH1B, 16 vs 4%; ALDH2 84 vs 44%; MTP 62 vs 72%, respectively; all P < 0.01). Comparing noncirrhosis to cirrhosis, the frequency of the potassium voltage‐gated channel subfamily Q member 1 (KCNQ1) genotype TT and adrenoceptor beta 3 (ADRB3) genotype TT was increased significantly in ALD‐related cirrhosis. In contrast, the patatin‐like phospholipase 3 (PNPLA3) genotype CC was decreased significantly in NAFLD‐related cirrhosis. A comparison of patients with and without HCC demonstrated that the KCNQ1 genotype TT was increased significantly in both HCC groups. In addition, associations between the KCNJ15 genotype GG and ALD‐HCC and the G allele of PNPLA3 and NAFLD‐HCC were identified.ConclusionsSNPs in genes related to ethanol and lipid metabolism clearly differed between patients with ALD and NAFLD. KCNQ1 might affect the progression and hepatocarcinogenesis in both ALD and NAFLD.

East Asian variant of aldehyde dehydrogenase 2 is related to worse cardioprotective results after coronary artery bypass grafting.

Aldehyde dehydrogenase 2 activity is associated with cardioprotection. Individuals carrying an East Asian variant of the ALDH2 genotype (ALDH2*2) have significantly reduced aldehyde dehydrogenase 2 activity. No previous studies have determined the effect of the ALDH2*2 genotype on cardioprotective results after coronary artery bypass grafting (CABG). In total, 207 patients who underwent selective off-pump CABG were prospectively enrolled. Their baseline characteristics and clinical results were collected. Preoperative and postoperative circulating oxidative stress levels (serum malondialdehyde adducts and hydroxynonenal adducts) were measured. After genotyping, the oxidative stress levels and clinical results were compared between the ALDH2*2 carriers and non-carriers. ALDH2*2 carriers exhibited higher levels of malondialdehyde (P = 0.02) and hydroxynonenal (P = 0.03) adducts after CABG. ALDH2*2 carriers had higher postoperative troponin I levels (P = 0.01) and 24-h inotropic scores (P = 0.02). The intensive care unit time (P = 0.03) and postoperative length of stay (P = 0.03) were longer in ALDH2*2 carriers. The postoperative pulmonary infection rate was higher (P = 0.03) in ALDH2*2 carriers. Patients with the ALDH2*2 genotype had higher postoperative oxidative stress levels and poorer clinical results after CABG. Special cardioprotective techniques should be considered for patients with a history of 'facial flushing' when performing CABG.

Correlation of Genetic Polymorphism, Alcoholic Beverage Type and Ethanol Metabolism

To explore the effects of ADH1B and ALDH2 gene polymorphism and type of alcoholic beverage on ethanol metabolism, to provide data support for cases involving the interpretation of ethanol metabolism or back calculation of blood ethanol concentration in forensic practice. A total of 81 volunteers were selected. The genotypes of ADH1B, ADH1C and ALDH2 were obtained by a multiplex SNaPshot genotyping method. Each subject was administered with 1.0 g/kg of alcohol. About 1 mL venous blood was collected before and after the alcohol consumption at 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h and 8 h, respectively. The concentrations of ethanol and acetaldehyde in blood were determined by headspace gas chromatography. The peak times of blood ethanol concentration （Tmax）, the peak mass concentrations of ethanol （Cmax）, the area under curve （AUC） of ethanol （AUCethanol）, AUCacetaldehyde and ethanol elimination rates （β） were calculated. In order to eliminate the influence of ADH1C, the ADH1C*1/*1 carriers were grouped based on the genotype of ADH1B and ALDH2. The data of each group were evaluated by one-way analysis of variance and pairwise comparison tests were performed by least significant difference method. The gene interactions were evaluated by two-way analysis of variance. Each parameter of three kinds of alcoholic beverage （white wine, red wine and beer） among groups was analysed by variance analysis with randomized block design. There were no differences in the value of Tmax and Cmax between the groups with different ADH1B and ALDH2 genotype. The differences in the values of AUCethanol, β and AUCacetaldehyde among some groups carrying different ADH1B and ALDH2 genotype had statistical significance, while no significant difference was observed in these parameters when one individual taking same dose of different alcoholic beverage type. The ethanol metabolism is associated with the related gene polymorphism, which is barely affected by alcoholic beverage type.

Validation of Alcohol Flushing Questionnaires in Determining Inactive Aldehyde Dehydrogenase-2 and Its Clinical Implication in Alcohol-Related Diseases.

Our aim was to validate alcohol flushing questionnaires in detecting inactive ALDH2 (ALDH2*1/*2 or ALDH2*2/*2). Two study sets were established; in study set 1, 210 healthy male subjects (age 22 to 59years) were enrolled; in study set 2, 756 subjects were enrolled who received esophagogastroduodenoscopy to evaluate their dyspeptic symptoms or as part of a gastric cancer screening program. Subjects in study sets 1 and 2 completed the modified alcohol flushing questionnaires of Yokoyama and colleagues (, ). Polymerase chain reaction-restriction fragment length polymorphism method was used to determine ALDH2 genotype. In study set 1, 29.0% (61 of 210) had inactive ALDH2. The sensitivity and specificity of the modified alcohol flushing questionnaire for detecting inactive ALDH2 were 95.1 and 76.5%, respectively. Drinking problems negatively correlated with positive alcohol flushing response and inactive ALDH2 (all p-values<0.05). In study set 2, the sensitivity and specificity of the alcohol flushing questionnaire for detecting inactive ALDH2 were 78.9 and 82.1%, respectively. Interestingly, drinking ≥7units/wk in men or ≥3.5units/wk in women significantly increased the risk of benign gastric ulcer (BGU) among positive alcohol flushers (odds ratio, 8.97; 95% confidence interval, 1.38 to 58.30), but not among negative alcohol flushers. Simple flushing questionnaires may be administered to the Korean population as a screening tool in detecting individuals who carry inactive ALDH2. Alcohol flushing response negatively correlates with drinking problems and can modify the risk for BGU by alcohol intake.

Slow-metabolizing ADH1B and inactive heterozygous ALDH2 increase vulnerability to fatty liver in Japanese men with alcohol dependence.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984, His48Arg) and aldehyde dehydrogenase-2 (ALDH2; rs671, Glu504Lys) affect body weight, body fat, and lipid metabolism in individuals with alcohol dependence, and the aim of this study was to identify their determinants in relation to the development of fatty liver. We evaluated associations between the presence of fatty liver and ADH1B and ALDH2 genotypes and other factors in 1604 Japanese men who had been admitted for treatment of alcohol dependence. Fatty liver was diagnosed when ultrasonography showed both hepatorenal contrast and liver brightness. Age-adjusted usual alcohol intake did not differ according to ADH1B or ALDH2 genotypes. A multivariate analysis showed that the adjusted odds ratio (OR, 95% confidence interval) of slow-metabolizing ADH1B Arg/Arg carriers was 1.61 (1.27-2.03) for fatty liver and 1.82 (1.37-2.41) for fatty liver with deep attenuation in comparison with the ADH1B His/Arg or His/His carriers, and that the OR of inactive heterozygous ALDH2 Glu/Lys carriers was 1.43 (1.08-1.91) for fatty liver and 1.84 (1.31-2.59) for fatty liver with deep attenuation in comparison with the ALDH2 Glu/Glu carriers. Younger age, shorter interval between the last drink and the ultrasound examination, larger body mass index, and absence of cirrhosis were identified as other positive determinants for fatty liver. The ADH1B Arg/Arg genotype and the ALDH2 Glu/Lys genotype were positive determinants of fatty liver in the subjects. These results suggest that slow ethanol and acetaldehyde metabolism accelerates the development of alcoholic fatty liver in heavy drinkers.

Investigating the Association between Alcohol and Risk of Head and Neck Cancer in Taiwan

Although alcohol is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature in several aspects. We analyzed detailed alcohol consumption data (amount and type of alcoholic beverage) of 811 HNC patients and 940 controls to evaluate the association between alcohol and HNC by HNC sites and by genotypes of ADH1B and ALDH2. Alcohol was associated with an increased HNC risk in a dose-response relationship, with the highest risk observed for hypopharyngeal cancer, followed by oropharyngeal and laryngeal cancers. Liquor showed a stronger positive association with HNC than beer and wine. The highest HNC risk occurred in individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. In our study population, 21.8% of HNCs, 55.7% of oropharyngeal cancers, and 89.1% of hypopharyngeal cancers could be attributed to alcohol. Alcohol accounted for 47.3% of HNCs among individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. The HNC risk associated with alcohol became comparable to that of never/occasional drinkers after ten or more years of cessation from regular alcohol drinking. In conclusion, alcohol use is associated with an increased HNC risk, particularly for individuals with slow ethanol metabolism. HNC incidence may be reduced by alcohol cessation.

Genetic polymorphisms of alcohol-metabolizing enzymes and their association with alcoholism risk, personality and anthropometric traits among Malaysian university students

Three single nucleotide polymorphisms (SNPs) in alcohol-metabolizing genes – ADH1B (Arg47His), ADH1C (Ile350Val) and ALDH2 (Glu504Lys) have been extensively associated with flush reaction and alcoholism. Therefore, we investigated the association of these three SNPs with alcohol-induced reactions (AIRs), alcoholism risk, personality and anthropometric traits among Malaysian university students. AIRs, Self-Rating of the Effects of Alcohol (SRE) and Ten-Item Personality were surveyed, anthropometric measurements and DNA samples were taken. Among 264 valid drinkers (111 males, 153 females; 229 ethnic Chinese, 35 ethnic Indians), the minor allele frequencies for ADH1B, ADH1C, ALDH2 among Chinese/Indians were .45/.07, .33/.40, .32/.41, respectively; distribution of ADH1B alleles significantly different between ethnicities. Current/former experiences of flushing, hives, heart palpitations after alcohol consumption; and sleepiness, headache reactions, early and overall SRE were significantly different between ethnicities and genders, respectively. Overall SRE score was associated with ADH1C and ALDH2 alleles. ‘Openness to Experiences’ was associated with ALDH2 genotypes and alleles; Glu/Glu or Glu carriers showed significantly higher means. ADH1B Arg/Arg and Arg carriers showed significantly higher total body and subcutaneous fats but association was abolished after controlling for ethnicity. In conclusion, gender and ethnicity, but not alcohol-metabolizing gene variants, play a role in influencing the manifestation of AIRs.

Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic effect of ALDH bright cell on peripheral ischemia

The autologous ALDH bright (ALDHbr) cell therapy for ischemic injury is clinically safe and effective, while the underlying mechanism remains elusive. Here, we demonstrated that the glycolysis dominant metabolism of ALDHbr cells is permissive to restore blood flow in an ischemic hind limb model compared with bone marrow mononuclear cells (BMNCs). PCR array analysis showed overtly elevated Aldh2 expression of ALDHbr cells following hypoxic challenge. Notably, ALDHbr cells therapy induced blood flow recovery in this model was reduced in case of ALDH2 deficiency. Moreover, significantly reduced glycolysis flux and increased reactive oxygen species (ROS) levels were detected in ALDHbr cell from Aldh2-/- mice. Compromised effect on blood flow recovery was also noticed post transplanting the human ALDHbr cell from ALDH2 deficient patients (GA or AA genotypes) in this ischemic hindlimb mice model. Taken together, our findings illustrate the indispensable role of ALDH2 in maintaining glycolysis dominant metabolism of ALDHbr cell and advocate that patient's Aldh2 genotype is a prerequisite for the efficacy of ALDHbr cell therapy for peripheral ischemia.

Alcohol consumption adjusted by aldehyde dehydrogenase 2 genotype: A potential risk factor for gastric cancer?

e15541 Background: The role of aldehyde dehydrogenase 2 (ALDH 2) in alcohol metabolism has been ascertained, yet the association between ALDH2 genotype and the carcinogenesis of gastric cancer remains controversy. Methods: We retrospectively collected data of 292 subjects hospitalized in Zhongshan Hospital in Shanghai during March 2016 to September 2016. All subjects were divided into case group (identified with gastric cancer by postoperative pathology) and control group. Distribution of aldehyde dehydrogenase 2 genotype, drinking status along with other clinical variables were compared. Logistic regression model included age, gender, smoking and drinking status, family history and ALDH2 genotype. Adjusted odds ratios (ORs) were calculated. Results: There was a significant elevation of alchohol consumption in case group (P = 0.033). Subjects with ALDH2 *1/*2 and *2/*2 genotype showed less inclination for drinking than ALDH2 *1/*1 (P &lt; 0.001). The risk for gastric cancer showed no differences among subjects with ALDH2 genotype adjusted drinking status [OR 1.121, 95% confidence interval (CI) 0.555-2.263 in Never/rare drinkers; OR 3.380, 95% CI 0.232-49.240 in Light drinkers and OR 2.416, 95% CI 0.326-14.151). Further analysis indicated that high body weight index (BMI) and heavy smoking were individual risk factors for gastric cancer among Light/heavy dringkers with ALDH2 *1/*2 or *2/*2 genotype (OR 84.736, P = 0.021 for BMI and OR 3.904, P = 0.037 for smoking). Conclusions: A dose-response relationship between alchohol consumption and risk for gastric cancer was observed in primary analysis. However ALDH2 genotype failed to modify the alchohol consumption. Our findings suggested that there might be other pathways to further explain the mechanisim of the role of alchohol consumption in carcinogenisis of gastric cancer.

A Bayesian Approach for Population Pharmacokinetic Modeling of Alcohol in Japanese Individuals

BackgroundBlood alcohol concentration data that were previously obtained from 34 healthy Japanese subjects with limited sampling times were reanalyzed. Characteristics of the data were that the concentrations were obtained from only the early part of the time-concentration curve. ObjectiveTo explore significant covariates for the population pharmacokinetic analysis of alcohol by incorporating external data using a Bayesian method, and to estimate effects of the covariates. MethodsThe data were analyzed using a Markov chain Monte Carlo Bayesian estimation with NONMEM 7.3 (ICON Clinical Research LLC, North Wales, Pennsylvania). Informative priors were obtained from the external study. ResultsA 1-compartment model with Michaelis-Menten elimination was used. The typical value for the apparent volume of distribution was 49.3 L at the age of 29.4 years. Volume of distribution was estimated to be 20.4 L smaller in subjects with the ALDH2*1/*2 genotype than in subjects with the ALDH2*1/*1 genotype. ConclusionsA population pharmacokinetic model for alcohol was updated. A Bayesian approach allowed interpretation of significant covariate relationships, even if the current dataset is not informative about all parameters. This is the first study reporting an estimate of the effect of the ALDH2 genotype in a PPK model.

Susceptibility to oral squamous cell carcinoma: correlation with variants of CYP1A1-MspI, GSTT1, GSTM1, ALDH2, EC-SOD and Lifestyle factors.

In order to investigate the association between polymorphisms in genes encoding metabolizing enzymes (CYP1A1-MspI, EC-SOD (extracellular superoxide dismutase), GSTT1, GSTM1, ALDH2), cigarette and alcohol consumption, and the risk of oral squamous cell carcinoma, we conducted a prospective case-control study comprised of 750 individuals with oral squamous cell carcinoma (OSCC) and 750 healthy individuals. Data about smoking and drinking habits were collected along with other demographic and clinical information. Peripheral blood samples were collected for DNA extraction, and polymerase chain reaction (PCR) and PCR-RFLP (restriction fragment length polymorphism) were used to determine genotypes of CYP1A1, EC-SOD, GSTT1, GSTM1, ALDH2. The results showed that smoking and alcohol consumption were significantly more common among patients than controls (p <0.05). There were significant differences in the genotype distribution for each locus between groups, with the CYP1A1 (m2/ m2), EC-SOD (C/G), GSTT1 [–], GSTM1 [–] and ALDH2 (non G/G) genotypes being more common among patients (p <0.05). Furthermore, the majority of patients had at least two or more variant genotypes, while controls had one or no variant genotype (p <0.05). Finally, multiple variant genotypes combined with smoking, drinking, or both smoking and drinking significantly increased the risk of OSCC, with greater increase for heavier smoking/drinking. In brief, genetic polymorphism of CYP1A1, EC-SOD, GSTT1, GSTM1, and ALDH2 and smoking and drinking history are closely associated with susceptibility to OSCC.

The causal effects of alcohol on lipoprotein subfraction and triglyceride levels using a Mendelian randomization analysis: The Nagahama study

BackgroundLight-to-moderate alcohol consumption may increase circulating high-density lipoprotein cholesterol (HDL-C) levels and decrease low-density lipoprotein cholesterol (LDL-C) levels. However, the effect of alcohol on biologically important lipoprotein subfractions remains largely unknown. Here we aimed to clarify the effects of alcohol on lipoprotein subfractions using a Mendelian randomization analysis. MethodsThe study subjects consisted of 8364 general Japanese individuals. The rs671 polymorphism in aldehyde dehydrogenase 2 gene, a rate-controlling enzyme of alcohol metabolism, was used as an instrumental variable. Lipoprotein subfractions were measured by a homogeneous assay. ResultsThe biologically active *1 allele of the ALDH2 genotype was strongly associated with alcohol consumption in men (p < 0.001). In a regression analysis adjusted for possible covariates, the *1 allele was positively associated with HDL-C even in a sub-analysis for HDL subfractions (HDL2-C: β = 0.082, p < 0.001; HDL3-C: β = 0.195, p < 0.001). In contrast, the *1 allele was inversely associated with total LDL-C levels (β = −0.049, p = 0.008), while its association with large-buoyant LDL-C (β = −0.124, p < 0.001) and small-dense LDL-C (β = 0.069, p < 0.001) was opposite. Therefore, the ratio of small-dense LDL to large-buoyant LDL exhibited a linear increase with the number of *1 alleles carried (β = 0.127, p < 0.001). Furthermore, the *1 allele was inversely associated with triglyceride levels in an analysis adjusted for LDL subfractions (β = −0.097, p < 0.001), but not for the total LDL (β = 0.014, p = 0.410). ConclusionsAlcohol may increase HDL-C levels irrespective of the particle size. Moreover, alcohol may decrease the total LDL-C, although the proportion of atherogenic small-dense LDL-C increased partially due to a potential inter-relationship with decreased triglyceride levels.

Duplex PCR-RFLP for the Simultaneous Genotyping of Single Nucleotide Polymorphisms in ADH1B and ALDH2 Genes.

Single nucleotide polymorphisms (SNPs) in ADH1B and ALDH2, which encode alcohol dehydrogenase 1B and aldehyde dehydrogenase 2, respectively, are responsible for ethanol-metabolizing activity and alcohol-related disease. We developed a simple and rapid polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method for the simultaneous genotyping of the genes in a single-tube reaction. Using an alkaline lysate of a human hair root as a template, SNP-containing regions of each gene were PCR-amplified simultaneously. The PCR products were directly applied to double restriction digestion, followed by agarose gel band analysis. The duplex PCR-RFLP allows for the simultaneous and accurate determination of the SNP genotypes of ADH1B and ALDH2 within 1.2 h.

ALDH2 polymorphism for the risk of cervical carcinogenesis.

To investigate the clinical significance of ALDH2 genetic polymorphisms in cervical carcinogenesis. ALDH2 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 195 cervical smear in exfoliated cervical cell samples using Real-Time polymerase chain reaction (PCR) System. The frequency for the AG+AA genotype was seven in the normal group (70.0 %), 16 in the LSIL group (57.1 %), and 27 in the HSIL group (90.0 %). A significant difference was found between the LSIL and HSIL groups (P = 0.0064). Patients with HSIL lesions frequently had high-risk HPV infections and concurrently belonged to the AG+AA group. ALDH2 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.

Tracing Jomon and Yayoi ancestries in Japan using ALDH2 and JC virus genotype distributions.

BackgroundAccording to the dual structure model, the modern Japanese ethnic population consists of a mixture of the Jomon people, who have existed in Japan since at least the New Stone Age, and the Yayoi people, who migrated to western Japan from China around the year 300 bc Some reports show that the Yayoi are linked to a mutation of the aldehyde dehydrogenase 2 gene (ALDH2).Recent viral studies indicate two major groups found in the Japanese population: a group with the CY genotype JC virus (JCV) and a group with the MY genotype JCV. It is unclear whether either genotype of the JC virus is related to the Jomon or Yayoi.In this study, we attempted to detect JCV genotypes and ALDH2 mutations from the DNA of 247 Japanese urine samples to clarify the relationship between the dual structure model and the JCV genotype through ALDH2 mutation analysis and JCV genotyping.FindingsThe ALDH2 polymorphism among 66 JC virus-positive samples was analyzed, and it was found that the ALDH2 variant is significantly higher in the population with CY genotype JCV (51.5 %) than in the population with the MY genotype (24.2 %) (p < 0.05).ConclusionFrom these findings, it may be inferred that the ALDH2 mutation, which is related to the Yayoi, is related to CY genotype JCV. When the Yayoi migrated to the Japanese archipelago, they brought the ALDH2 mutation as well as the CY genotype JCV.

Characterization of polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 and relationship to the alcoholism in a Colombian population

Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism. ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells. Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender) were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant. This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2 * 2, CYP2E1 * 1 combined with genotype homozygous ALDH2 * 1 found in this study could be leading to the population to a potential risk to alcoholism.