Alcohol Dehydrogenase Polymorphism Research Articles

Impact of Alcohol Dehydrogenase 7 Polymorphism and Alcohol Consumption on Risk of Head and Neck Squamous Cell Carcinoma: A Korean Case-Control Study.

Head and neck squamous cell carcinoma (HNSCC) is closely associated with alcohol consumption and individual genetic susceptibility, such as single nucleotide polymorphism (SNP) of alcohol dehydrogenase (ADH). This study aimed to investigate the association of ADH7 SNPs with the risk of HNSCC. We analyzed ADH7 rs1573496C>G, rs3737482T>C, rs1154460G>A, and rs284787T>C SNPs in 250 patients with HNSCC and 322 controls in the Korean populations. Genotyping was conducted using the TaqMan assay. Linkage disequilibrium and haplotypes were analyzed. The odds ratios (OR) and 95% confidence intervals (CI) of the CT and CC genotypes of ADH7 rs3737482T>C were 0.48 (0.29-0.78) and 0.69 (0.49-0.96), indicating a significantly decreased risk. In SNP of rs1154460G>A, the OR and 95% CI of the AA genotype was 1.63 (1.11-2.40), showing a significant increase in the risk. Furthermore, SNPs of ADH7 rs3737482T>C and ADH7 rs1154460G>A exhibit synergistic interactions with alcohol composition on the risk of HNSCC. None of the haplotypes were associated with the risk of HNSCC. ADH7 rs3737482T>C and rs1154460G>A SNPs are associated with the risk of development of HNSCC in Koreans. They could serve as molecular biological markers to screen high-risk groups for HNSCC.

Genetic Polymorphism of Alcohol Dehydrogenase 2 (ADH1B) in Association with Alcohol Consumption in Nepalese Population

Genetic Polymorphism of Alcohol Dehydrogenase 2 (ADH1B) in Association with Alcohol Consumption in Nepalese Population

Effects of Gene Polymorphisms, Metabolic Activity, and Content of Alcohol Dehydrogenase and Acetaldehyde Dehydrogenases on Prognosis of Hepatocellular Carcinoma Patients.

Alcohol dehydrogenase and acetaldehyde dehydrogenases have been associated with hepatocellular carcinoma, but how alcohol dehydrogenase and acetaldehyde dehydrogenases alter the prognosis of hepatocellular carcinoma have not been completely elucidated. Metabolic activities, gene polymorphisms, and content of alcohol dehydrogenase and acetaldehyde dehydrogenases were determined in 68 fibrotic livers from hepatocellular carcinoma patients. These characteristics were then correlated with clinical features and prognosis in these patients. The median survival time of the ALDH-high activity group (727 days) was increased by 128% compared with that of ALDH-low activity group (319 days), and there was a significant negative correlation between the activity of acetaldehyde dehydrogenases and the level of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. There was no difference in survival time between ALDH2-high and ALDH2-low expression group, though the activity of acetaldehyde dehydrogenases had correlation with the content of ALDH2 (r = 0.6887, P < .001). Mutation at ALDH2rs671 significantly decreased both the activity and content of acetalde- hyde dehydrogenases, but the polymorphism had no relationship with progression of hepatocellular carcinoma patients. In addition, the activity and 3 polymorphisms of alcohol dehydrogenase had no effect on overall survival. Mutation at ADH1Crs698 significantly decreased both the activity and content of alcohol dehydrogenase (P < .05), mutation at ADH1C rs2241894 had an inverse effect, and mutation at ADH1B rs1229984 increased activity but did not affect content. The activity of alcohol dehydrogenase had a moderate cor- relation with the content of ADH1A and ADH1C in livers (P < .05). Low activity of acetaldehyde dehydrogenases in livers correlates with poor prognosis and clinical progression in hepatocel- lular carcinoma patients, and both gene polymorphisms and content influence its metabolic activity.

Possibilities of the early diagnosis and prognosis of complicated clinical forms of chronic pancreatitis

AIM: This study aimed to improve the methods for the diagnosis of complicated clinical forms of chronic pancreatitis (CP) by evaluating the clinical significance of the polymorphisms of the genes of cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1), transmembrane regulator of cystic fibrosis (CFTR), and alcohol dehydrogenase (ADH) in patients with complicated and uncomplicated forms of CP.&#x0D; MATERIALS AND METHODS: The study was carried out on the clinical base of the Department of Hospital Surgery, Ryazan State Medical University, Center for Surgery of Liver, Pancreas, and Biliary Tract in Ryazan in 20142019. A total of 108 patients of both genders aged 2565 years were examined. Of these patients, 38 were surgically treated for complicated CP, 20 had complicated CP without surgery, and 50 had uncomplicated CP (control group). A comparative clinical study with the control group of patients was performed, and the genotype was simultaneously determined on days 1 and 10 under controlled laboratory parameters. DNA was isolated from the leukocytes of the whole blood by using a DNA-expressing blood reagent (OOO NPF Litekh, Russia) for further analysis.&#x0D; RESULTS: No polymorphism of cationic trypsinogen PRSS1 gene and cystic fibrosis-2 CFTR2 gene was found. The predictive value of these polymorphisms was insignificant. For the polymorphism of CFTR1 cystic fibrosis-1 gene, the odds ratio was 0.444, but this finding was not significant. Among patients with the complicated clinical forms of CP, mutations were observed in the PRSS1 cationic trypsinogen gene (c2 = 6.453, p = 0.012) and ADH (c2=14.176, p = 0.001). Conversely, they were not detected in the CFTR-1 gene (c2 = 0.873, p = 0.351), CFTR-2 (c2 was not determined), and SPINK1 (c2 = 0.873, p = 0.351). The polymorphisms of the ADH and PRSS1 genes of cationic trypsinogen were associated with more evident structural changes in the parenchyma and ductal system of the pancreas. They also had a higher likelihood of complications, severe disease course, and a lower efficiency of conservative treatment. The polymorphism of the ADH gene increased the risk of the development of the cystic form of CP (c2 = 5.898, p = 0.016).&#x0D; CONCLUSION: The polymorphism of ADH and cationic trypsinogen genes should be determined and used for the complex diagnosis of CP to specify indications for the surgical treatment of patients with CP.

Association of alcohol dehydrogenase and aldehyde dehydrogenase Polymorphism with Spontaneous Deep Intracerebral Haemorrhage in the Taiwan population

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) encode essential alcohol-metabolizing enzymes. While alcohol use is associated with spontaneously deep intracerebral haemorrhage (SDICH), particularly in males, the activities and genetic variants of ADH and ALDH may affect SDICH development. This case-control study was conducted to identify the interaction of alcohol use and SDICH with five single-nucleotide polymorphisms (SNPs): ADH1B rs1229984, ADH1C rs2241894, ALDH2 rs671, ALDH2 rs886205, and ALDH2 rs4648328. We enrolled 208 patients with SDICH and 244 healthy controls in a Taiwanese population. ALDH2 rs671 was significantly associated with SDICH in the dominant (P < 0.001) and additive models (P = 0.007). ALDH2 rs4648328 was borderline significantly associated with SDICH in the recessive (P = 0.024) or additive models (P = 0.030). In alcohol-using patients, the ALDH2 rs671 GG genotype was associated with SDICH risk compared to the GA+AA genotype (P = 0.010). ADH1B rs1229984, ADH1C rs2241894, and ALDH2 rs886205 did not demonstrate association with SDICH. Thus, the ALDH2 rs671 GG genotype is a risk factor for SDICH. Because the genetic distributions of ALDH2 rs671 exhibited strong ethnic heterogeneity, further studies in different populations are needed to validate these findings.

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.

Genetic variations of aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B are associated with the etiology of atrial fibrillation in Japanese.

BackgroundAlcohol consumption and oxidative stress are well-known risk factors for developing atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes encoding enzymes of alcohol and reactive aldehyde metabolism, respectively, are prevalent among East Asians. Here, we examined whether these SNPs were associated with AF in Japanese patients.Methods and resultsFive hundred seventy-seven Japanese patients with AF undergoing catheter ablation and 1935 controls at Hiroshima University Hospital were studied. Alcohol consumption habits, medical history, electrocardiogram (EKG), electrophysiology and cardiac echocardiography were reviewed. Patients were also genotyped for ALDH2 (rs671) and ADH1B (rs1229984). A significant linear correlation was found between ALDH2 genotype and mean alcohol intake (P = 1.7 × 10−6). Further, ALDH2 (rs671) was associated with AF (P = 7.6 × 10−4, odds ratio [OR] = 0.6). Frequency of the ALDH2 SNP allele A which limits acetaldehyde metabolism was lower in patients with AF (18.8%) than in controls (23.5%). In contrast, we found that the frequencies of the ADH1B SNP genotypes were similar in patients with AF and in controls. Subset analysis among the 182 patients with lone AF and 914 controls (control II) (<60 years of age and without hypertension), both ALDH2 and ADH1B SNPs were significantly associated with AF (P = 0.013, OR = 0.7; P = 0.0007, OR = 1.4, respectively). The frequency of the dysfunctional allele A of ALDH2 was significantly lower and the dysfunctional allele G of ADH1B was significantly higher in patients with lone AF than in control II (ALDH2 A allele frequency = 0.176 vs 0.235, OR = 1.3, P = 0.013, ADH1B SNP G allele frequency = 0.286 vs 0.220, OR = 1.4, P = 0.0007).ConclusionsWhen considering all patients enrolled, the dysfunctional ALDH2 allele was negatively associated with AF. When examining a subset of patients with lone AF, the dysfunctional ALDH2 allele was negatively associated with AF and the slower metabolizing ADH1B allele was positively associated with AF. Hence, prolonged metabolic conversion of alcohol to acetaldehyde may be associated with the occurrence of AF in the Japanese and other East Asian populations.

Interaction of vitamin A supplementation level with ADH1C genotype on intramuscular fat in beef steers

Previously, the single nucleotide polymorphism in alcohol dehydrogenase (ADH1C c.-64T>C) was shown to have an association with intramuscular fat (IMF) in the longissimus thoracis (LT) muscle when vitamin A was limited in finishing rations of beef steers. The purpose of this study was to determine the optimum vitamin A supplementation level, in combination with ADH1C genotype, to increase IMF of the LT muscle. In total, 45 TT genotype, 45 CT and 27 CC Black Angus crossbred steers were backgrounded on a commercial ration containing 3360 IU vitamin A/kg dry matter (DM). During finishing, the steers were randomly assigned to one of three vitamin A treatments at 25%, 50% and 75% of the National Research Council recommendation of 2200 IU/kg DM. Treatments were administered via an oral bolus. Carcass quality was evaluated and a sample from the LT muscle was collected for analysis of IMF. A treatment×genotype interaction (P=0.04) was observed for IMF; TT steers on the 75% treatment had higher IMF relative to CT and CC steers on the same treatment. Western blot analysis showed that TT steers had higher (P=0.02) ADH1C protein expression in hepatic tissue. Previously, TT steers exhibited increased IMF when fed limited vitamin A. In the current study, the lack of variation in IMF between treatments and genotypes at the lower vitamin A treatment levels was likely due to the majority of the steers grading Canada AAA (USDA Choice). However, the western blot data supports that TT steers are expected to have higher IMF deposition, due to an increased production of ADH1C. The interaction between ADH1C genotype and vitamin A supplementation level has the potential for use in marker-assisted management programs to target niche markets based on increased marbling.

Clinical features and prognostic factors in patients with head and neck cancer: Results from a multicentric study

BackgroundThe purpose of this study is to evaluate whether demographics, lifestyle habits, clinical data and alcohol dehydrogenase polymorphisms rs1229984 and rs1573496 associated with first primary head and neck (HNC) are associated with overall survival, recurrence, and second primary cancer (SPC). MethodsWe conducted a follow-up study in five centres including 801 cases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for overall survival, recurrence and SPC. ResultsFive-years overall survival was 62% for HNC cases, 55% for oral cavity, 53% for oropharynx, 41% for hypopharynx, and 71% for larynx. Predictors of survival were older ages (HR=1.18 for 5 years increase; CI: 1.07–1.30), higher tumour stage (HR=4.16; CI: 2.49–6.96), and high alcohol consumption (HR=3.93; CI: 1.79–8.63). A combined therapy (HR=3.29; CI: 1.18–9.13) was associated with a worst prognosis for oral cavity cancer. The only predictor was higher tumour stage (HR=2.25; CI: 1.26–4.03) for recurrence, and duration of smoking (HR=1.91; CI: 1.00–3.68) for SPC. ADH1B rs1229984 polymorphism HRs for HNC and oesophageal cancer death and for alcohol related cancer death were 0.67 (95% CI: 0.42–1.08), and 0.64 (95% CI: 0.40–1.03), respectively. ConclusionsThe survival expectation differs among HNC sites. Increasing age and stage, and high alcohol consumption were unfavourable predictors of HNC survival overall. Duration of tobacco consumption before the first primary tumour was a risk factor for SPC.

Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study.

The association between alcohol consumption, genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and gastric cancer risk is not completely understood. We investigated the association between ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms, alcohol consumption and the risk of gastric cancer among Japanese subjects in a population-based, nested, case-control study (1990-2004). Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 457 new gastric cancer cases matched to 457 controls were used in the analysis. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using logistic regression models. No association was observed between alcohol consumption, ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms and gastric cancer risk. However, considering gene-environmental interaction, ADH1C G allele carriers who drink ≥150 g/week of ethanol had a 2.5-fold increased risk of gastric cancer (OR = 2.54, 95% CI = 1.05-6.17) relative to AA genotype carriers who drink 0 to <150 g/week (P for interaction = 0.02). ALDH2 A allele carriers who drink ≥150 g/week also had an increased risk (OR = 2.08, 95% CI = 1.05-4.12) relative to GG genotype carriers who drink 0 to < 150 g/week (P for interaction = 0.08). To find the relation between alcohol consumption and gastric cancer risk, it is important to consider both alcohol consumption level and ADH1C and ALDH2 polymorphisms.

Subjective response to alcohol and ADH polymorphisms in a select sample of young adult male East Indians and Africans in Trinidad and Tobago.

Level of response to alcohol has been associated with risk of alcohol dependence in a number of ethnic groups. In the present study, subjective and objective responses to alcohol were evaluated in Indo-Trinidadians (Indo-T) and Afro-Trinidadians (Afro-T). Associations of alcohol dehydrogenase polymorphisms with response to alcohol, using the Subjective High Assessment Scale (SHAS), and breath alcohol concentrations (BrAC) were tested. Regular male drinkers without alcohol dependence (n = 112) ages 18-25 years participated in alcohol challenge sessions consisting of placebo and two doses of alcohol (target BrAC: 0 g/dl for placebo, .04 g/dl low dose, and .08 g/dl high dose) and genotyped for variants in ADH1B*3 and ADH1C*2. Indo-T had significantly higher BrAC, pulse rates, and cortisol levels when compared with Afro-T but did not have significantly higher SHAS values. Higher responses on the SHAS items muddle/confused and nauseated were significantly associated with the presence of at least one ADH1B*3 allele following the high dose of alcohol in Afro-T. Indo-T with at least one ADH1C*2 allele displayed significantly different Drug × Time interactions for the SHAS item effects of alcohol at the low dose and for the SHAS items clumsy, muddle/confused, effects of alcohol, floating, drunk, and total at the high dose from Indo-T with two ADH1C*1 alleles. This is the first study that has investigated individual sensitivity to alcohol in a Caribbean population and in people of East Indian descent. Indo-T with at least one ADH1C*2 allele may be at higher risk for heavy drinking by feeling less of the effects of alcohol, including nausea. In Afro-T, having at least one ADH1B*3 allele appears to exert a protective effect by enhancing the unpleasant effects of alcohol, such as nausea and confusion.

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy. A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled. Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

Evaluation of the Influence of Alcohol Dehydrogenase Polymorphisms on Alcohol Elimination Rates in African Americans

The relationship between alcohol dehydrogenase (ADH) polymorphisms and alcohol use disorders in populations of African descent has not been clearly established. This study examined the effect of ADH1B polymorphisms on alcohol metabolism and subjective response, following intravenous (IV) alcohol administration, and the influence of gender, recent drinking history, and family history of alcoholism (FHA), in nondependent African American drinkers. The sample included eighty-seven 21- to 35-year-old, light social drinkers of African descent. Participants included 39 sib pairs, 2 sibships with 3 siblings each, and 3 individuals who were not part of a sibship. Participants received infusions via the use of the clamp method that refers to the goal of controlling breath alcohol concentration in 2 randomized sessions at 0.06 g% ethanol and 0 mg% (placebo), and a battery of subjective scales at predefined time points. Dependent measures included alcohol elimination rates (AERs), alcohol disappearance rates (ADRs), subjective measures peak scores, and area under the curve. General linear model and mixed models were performed to examine the relationship between ADH1B genotype, dependent measures, and influence of covariates. Participants with ADH1B1/1 genotypes showed higher number of drinks (p = 0.023) and drinks per drinking day (p = 0.009) compared with the persons with ADH1B1/3 genotype. AER (adjusted for body weight) was higher in ADH1B*1 homozygotes (p = 0.045) compared with ADH1B1/3 heterozygotes. ADR differed significantly between males and females (p = 0.002), regardless of body weight (p = 0.004) and lean body mass (p < 0.001) adjustments. Although a few subjective measures differed across genotype, all measures were higher in alcohol sessions compared with placebo sessions (p < 0.001). These observations were mediated by drinks per drinking day, gender, and FHA. ADH1B polymorphism had a marginal effect on alcohol pharmacokinetics following IV alcohol administration in nondependent drinkers of African descent. Session (alcohol vs. placebo) and ADH1B genotype did, however, influence subjective response to alcohol with some variation by gender, FHA, and drinks per drinking day.

Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case–control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA+AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR=1.20, 95%CI: 1.03–1.40, P=0.021; MI: RR=1.32, 95%CI: 1.11–1.57, P=0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR=0.92, 95%CI: 0.73–1.15, P=0.445; MI: RR=0.93, 95%CI: 0.84–1.03, P=0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.

Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis

Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08-2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis.

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 alcohol dehydrogenase polymorphisms and life‐style factors with excessive alcohol intake within the Spanish population (EPIC‐Spain)

To analyse associations between alcohol dehydrogenase (ADH) polymorphisms and alcohol intake in Spanish men and women. We analysed the relationship between 21 genetic variants in ADH genes and excessive alcohol intake in both men and women. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array and a sex-stratified analysis was performed. Ethanol intake was calculated using a validated dietary history questionnaire. Heavy consumers of alcohol (≥70 g/day in men, ≥42 g/day in women) (653 cases) and very low or non-consumers (<2 g/day) (880 controls) from the Spanish cohort of the European Prospective Investigation into Cancer (EPIC). We found statistically significant associations between alcohol intake and known life-style factors; namely, smoking and food energy intake (meat and fruit/seeds) in both men and women, as well as with physical activity in women and educational level in men. Additionally, we found that a non-synonymous coding SNP in ADH1B (rs1229984) is associated inversely with excessive alcohol intake in men [odds ratio (OR) = 0.19, 95% confidence interval (CI) = 0.11-0.33; P = 4.77E(-10) ) and women (OR = 0.48, 95% CI = 0.27-0.83; P = 0.0067). Furthermore, ADH6 rs3857224 was found associated with heavy alcohol intake in women (OR = 1.61, 95% CI = 1.21-2.14; P = 1.01E(-3) ), but not in men. In the Spanish population, the single nucleotide polymorphism of alcohol dehydrogenase ADH1B, rs1229984, is associated inversely with alcohol intake in both men and women. Another polymorphism of ADH6, rs3857224, is associated with heavy alcohol intake in women.

Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn

Fetal alcohol spectrum disorders (FASDs) are a common cause of intellectual impairment and birth defects. More recently, prenatal alcohol exposure (PAE) has been found to be a risk factor for fetal mortality, stillbirth and infant and child mortality. This has led to increased concern about detection and management of PAE. One to 2 h after maternal ingestion, fetal blood alcohol concentrations (BACs) reach levels nearly equivalent to maternal levels. Ethanol elimination by the fetus is impaired because of reduced metabolic capacity. Fetal exposure time is prolonged owing to the reuptake of amniotic-fluid containing ethanol by the fetus. Alcohol elimination from the fetus relies on the mother's metabolic capacity. Metabolic capacity among pregnant women varies eightfold (from 0.0025 to 0.02 g dl(-1) h(-1)), which may help explain how similar amounts of ethanol consumption during pregnancy results in widely varying phenotypic presentations of FASD. At birth physiological changes alter the neonate's metabolic capacity and it rapidly rises to a mean value of 83.5% of the mother's capacity. FASDs are highly recurrent and younger siblings have increased risk. Detection of prenatal alcohol use offers an important opportunity for office-based interventions to decrease exposure for the remainder of pregnancy and identification of women who need substance abuse treatment. Mothers of children with FAS have been found to drink faster, get drunk quicker and to have higher BACs. A modest increase in the prevalence of a polymorphism of alcohol dehydrogenase, which increases susceptibility to adverse outcomes from PAE has been reported. Lastly, detection of alcohol use and appropriate management would decrease risk from PAE for subsequent pregnancies.

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

ObjectiveFirst, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk.MethodsWe conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011.ResultsCompared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10–0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33–0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12–0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98–1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90–1.27; p for heterogeneity: 0.098)].ConclusionThe well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation.

An association study between polymorphism of alcohol dehydrogenase (ADH1B), aldehyde dehydrogenase (ALDH2), cytochrome (CYP4502E1), Catechol-O- Methyltransferase (COMT) and 5-hydroxytryptamine transporter (5-HTT) genes in Yunnan Han population with alcohol dependence

Alcohol dependence (AD) is a complex disease resulting from the inheritance of several susceptible genes and multiple environmental determinants. The aim of thisstudy was to identify the genetic risk factors which include alcohol metabolizing genes and neurotransmitter related genes for alcoholism in Yunnan Han population. Eight allelic variants of five genes were genotyped from 332 Yunnan Han individuals (including 118 alcohol-dependent patients (DSM-IV criteria) and 214 controls) using PCR-RFLP method. Those polymorphic sites included alcohol dehydrogenase (ADH1B), aldehyde dehydrogenase (ALDH2), cytochrome P-4502E1 (CYP2E1) PstI, Catechol-O-Methyltransferase (COMT) rs2075507 (5’region), rs737865 (intron1), rs4680 (Val158Met), rs165599 (3’region) and serotonin transporter (5-HTTLPR). Both genotype and allele frequencies of ALDH2 and CYP4502E1 as well as the allele frequency of ADH1B gene differed significantly between AD group and control group. The proportion of ALDH2 *1/*2 genotype and *2 allele was significantly smaller in patients than that in controls (χ2 = 6.554, p = 0.038; χ2 = 4.906, p = 0.027), while the proportion of c2 allele of CYP4502E1 was significantly higher (χ2 = 4.410, p = 0.036). Compared with the controls, the frequencies of the 5-HTTLPR L/L genotype and COMT rs737865 C/C genotype were significantly lower in AD group. Twelve COMT haplotypes (rs2075507, rs737865, rs4680 and rs165599) defined as H1 to H12 were obtained in this major minority population. The prevalence of the haplotype H1 ‘‘A-C-A-A’’ was significantly greater in alcoholics than the prevalence in their respective control group. There were no significant differences in the genotype frequencies of the COMT rs2075507, rs4680 and rs165599 polymorphisms between alcoholics and controls. COMT rs2075507 and rs737865 polymorphisms were in complete linkage disequilibrium in Han population of Yunnan Province. This study indicates that polymorphisms of ADH1B, ALDH2, CYP4502E1, COMT and 5-HTT were significantly associated with AD in Han majority. The ADH1B *2, ALDH2 *2 alleles, 5-HTTLPR L/L genotype and C/C genotype of the COMT rs737865 polymorphism had an important role in reducing the risk of AD while the c2 allele of CYP4502E1 increased the risk of AD. Therefore, the A-C-A-A haplotype may be a dangerous factor leading to AD. Key words: Yunnan Han population, polymorphism, alcohol dependence, genetic risk factor.