ADH1B Polymorphisms Research Articles

Genetic Polymorphisms in ADH1B and ALDH2 Are Associated with Colorectal Tumors in Japan: A Case-Control Study

Background: Unlike with esophageal cancer, acetaldehyde levels and genetic polymorphisms in alcohol dehydrogenase have not yet been shown to be contributing factors for colorectal cancer (CRC). This study aimed to clarify the mechanism of CRC development related to alcohol consumption and to the presence of genetic polymorphisms in the alcohol dehydrogenase, ADH1B and aldehyde dehydrogenase, ALDH2. Methods: This was a case-control study (221 cases and 179 controls) in patients with adenomas and intramucosal tumors who underwent endoscopic removal of all tumors. The amount of alcohol consumption was determined using a self-recorded questionnaire, and the tumor information was obtained from colonoscopy results. Blood samples were taken to analyze the following polymorphisms: ALDH2 Glu504Lys and ADH1B His48Arg. Results: The polymorphisms in ADH1B and ALDH2 had little influence on the development of colorectal adenoma or intramucosal cancer. Patients with ALDH2 (Glu/Glu) were more tolerant of alcohol than those with ALDH2 (Glu/Lys and Lys/Lys). Next, we examined certain combinations of the ADH1B genotypes. In the ALDH2 (Glu/Glu) group, an increased risk (OR = 3.4; 95% CI 1.4 - 8.4; P = 0.009) was observed among moderate/heavy drinkers with ADH1B (His/His). In the ALDH2 (Glu/Lys and Lys/Lys) group, an increased risk (OR = 4.2; 95% CI 1.1 - 16.7; P = 0.041) was found among moderate/heavy drinkers with ADH1B (Arg/His and Arg/Arg). Conclusions: ADH1B and ALDH2 activity may be involved in the development of CRC.

Nobody Is Perfect: Comparison of the Accuracy of PCR-RFLP and KASP™ Method for Genotyping. ADH1B and FTO Polymorphisms as Examples

DNA genotyping is among the most common analyses currently performed in scientific research. Two high-throughput genotyping techniques are widely used – the “classic” PCR-RFLP and probe-based methods such as TaqMan® PCR assay or KASP™ genotyping. The probe-based techniques are claimed to be more accurate than PCR-RFLP; however, the evidence for this claim is sparse. We have directly compared results of genotyping of two SNPs (rs1229984 and rs17817449) obtained by the PCR-RFLP and KASP™ in 1,502 adult Caucasians. The results were identical in 97.3 % and 95.9 % cases, respectively. Discrepancies (either different results or result obtained with one but not with the other method) were addressed by confirmatory analysis using direct sequencing. The sequencing revealed that both methods can give incorrect results, but the frequency of incorrect genotyping of rs1229984 and rs17817449 was very low for both methods – 0.1 % and 0.5 %, respectively, for PCR-RFLP and 0.1 % and 0.3 %, respectively, for KASP™. These results confirm that the KASP™ technique is slightly more accurate, but it achieves slightly lower call rates than PCR-RFLP. When carefully set up, both PCR-RFLP and KASP™ could have accuracy of 99.5 % or higher.

Effects of genetic variants of ADH1B and ALDH2 and social network on continued alcohol drinking among young adolescents in Taiwan

BackgroundThis study aimed (i) to evaluate the effects of genetic variants of ADH1B and ALDH2 and social network position on continued alcohol use in early adolescence, and (ii) to explore possible moderating role of pubertal development on genetic effects. MethodsThe sample comprised 496 children who ever drank alcohol before the ages of 10–12. Information pertaining to sociodemographic background, pubertal development, parental drinking, alcohol and tobacco use, alcohol-metabolizing genes, and nominated best friends was collected in four waves of assessment. Polymorphisms of ADH1B (rs1229984) and ALDH2 (rs671) were genotyped. The latent class analysis was first used to characterize longitudinal alcohol use pattern, followed by the multinomial logistic regression analyses to assess its association with genes, pubertal development, and social network. ResultsThree distinct classes of alcohol users (i.e. ex-drinkers, sporadic drinkers, and continued drinkers) were derived from alcohol-experienced children. Both alcohol-metabolizing genes appear to have protective effects, yet such relationships were only significant for youngsters in pre-to-early pubertal stage: the adjusted odds ratio (aOR) of ADH1B fast-genotype for sporadic drinkers was 0.46 and that of ALDH2 slow-genotype for both sporadic and continued drinkers was 0.47 and 0.42, respectively. Children having the bridge position in their peer network were more likely to be sporadic drinkers (aOR=4.15) and continued drinkers (aOR=3.16). ConclusionsOur results illustrate a potential moderating effect of pubertal development on the protective influence of alcohol-metabolizing genes on subsequent alcohol use among alcohol-experienced children as well as the independent contribution of early life's social network to their alcohol involvement.

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.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees

BackgroundAlthough alcohol-related disorders (ARD) have been shown to be accompanied by comorbid depressive and anxiety disorders, and alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms, have been associated with an increased risk of ARD, no studies have been conducted to evaluate the associations between these genetic polymorphisms and anxiety or depression. MethodA total of 1944 Japanese workers were interviewed regarding their depressive and anxiety disorders, including suicidality, by a brief psychiatric structured interview (MINI). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphism combinations with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and anxiety/depressive disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of two enzyme genotypes (Group I–V, in order from the lowest alcohol sensitivity). ResultsThose with ALDH2*1/*1 and ADH1B*1/*1 were likely to be at an increased risk of depressive and anxiety disorders as well as ARD. This tendency was more apparent among non-drinkers (OR 9.20, 95% CI 1.66–50.89). No adverse effects of ALDH2 or ADH1B alone were observed with mental disorder risks. Likewise, analyses conducted combining job rank and genetic alcohol sensitivity showed no material associations with such risks. ConclusionsGenetic alcohol sensitivity, especially that with the genotype combination of ALDH2*1/*1 and ADH1B*1/*1, was significantly associated with an increased risk of depressive and anxiety disorders as well as ARD.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms as indicator of mental disorders in Japanese employees.

Alcohol-related disorders (ARD) have been shown to be accompanied by a variety of other comorbid mental disorders. This study evaluated the associations between a variety of mental disorders and genetic alcohol sensitivity. A total of 1944 Japanese workers were interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview (M.I.N.I.). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphisms' combination with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and mental disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of ADH1B and ALDH2 genotypes (Group I-V in order starting from the lowest alcohol sensitivity). Those with ALDH2 *1/*1 and ADH1B *1/*1 or with ALDH2 *1/*1 and ADH1B *1/*2,*2/*2 (low sensitivity) were significantly or nearly significantly associated with an increased risk of ARD compared with those with ALDH2 *1/*2 and ADH1B *1/*2,*2/*2 as a reference. Those with ALDH2 *1/*1 and ADH1B *1/*1 were also likely to be at an increased risk of any mental disorder except ARD, as well as disorders without comorbid ARD. This tendency was more apparent among women (OR 11.94, 95% CI 0.73-195.63) and non-drinkers (OR 5.43, 95% CI 1.05-28.23). The genotype combination of ALDH2 *1/*1 and ADH1B *1/*1 is significantly associated with an increased risk of any mental disorder, especially ARD. Non-drinkers or women with ALDH2 *1/*1 and ADH1B *1/*1 are likely to suffer from any mental disorder except ARD.

The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer

Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1+ *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2+ *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

Functional polymorphism in aldehyde dehydrogenase-2 gene associated with risk of tuberculosis

BackgroundThe well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde. We investigated possible involvement of these functional polymorphisms in other common complex-trait diseases.MethodsThe genetic effects of these two polymorphisms on hepatitis, asthma, type-2 diabetes mellitus (T2DM), and tuberculosis (TB) were examined in a Korean population.ResultsWe demonstrated that the well-known functional polymorphism of a primary alcohol-metabolizing enzyme (ALDH2 Glu487Lys) has a strong genetic association with the risk of TB. The frequency of the minor allele (ALDH2*487Lys) was found to be much lower in TB patients (freq. = 0.099/n = 477) than among controls (freq. = 0.162/n = 796) (P = 0.00001, OR (95% confidential interval) = 0.57 (0.45-0.74)). Our data may indicate that TB was once an endemic disease, which exerted selection pressure for higher frequencies of ALDH2*487Lys in Asian populations. In addition, the calculated attributable fraction (AF) indicates that 39.5% of TB patients can attribute their disease to the detrimental effects of ALDH2Glu487Glu.ConclusionOur results suggest that this polymorphism is one of the genetic components of TB, at least in the Korean population.

EPA-0382 – Genetic alcohol sensitivity as an indicator of mental disorders

Objective To evaluate the association between genetic alcohol sensitivity ( ADH1B and ALDH2 polymorphisms) and mental disorders. Method A total of 1945 prefectural civil servants were screened and interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview. The mental disorders include major depressive disorder, dysthymia, suicidal risk, manic episode, panic disorder, agora phobia, social phobia, specific phobia, obsessive-compulsive disorder, general anxiety disorder, alcohol dependence/abuse, substance dependence/abuse, anorexia nervosa, anorexia bulimia, and PTSD. Genomic DNA was extracted from blood samples. TaqMan? SNP genotyping assays were used for the following (gene, SNP, assay ID): ADH1B , rs1229984, C_2688467_20; ALDH2 , rs671, C_11703892_10. Logistic regression analysis was used to evaluate those genetic polymorphisms and mental disorders adjusting for sex, age, and job rank. Results Alcohol sensitivity was genetically classified into five domains according to the combination of ADH1B and ALDH2 genotypes (type A, B, C, D and E). Preliminary analysis using 497 samples showed that low alcohol sensitivity (type A and B combined) was significantly associated with alcohol dependence/abuse (OR 2.71, 95% CI 1.44-5.10) compared to high sensitivity (type C, D, and E combined). Low alcohol sensitivity also showed non-significant modest association with any mental disorders except alcohol-related disorders (OR 1.99, 95% CI 0.72-5.48). Conclusions Low alcohol sensitivity might be associated with mental disorders, especially with alcohol-related disorders. Since the analysis has not been finished yet, the complete results will be shown in the congress.

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.

Population pharmacokinetics and pharmacogenetics of alcohol in Chinese and Indians in Singapore

Interindividual variability in alcohol pharmacokinetics is influenced by a number of factors, including polymorphisms in genes mediating alcohol pharmacology, ethnicity, sex and body size. Several studies have evaluated the population pharmacokinetics of alcohol from breath alcohol measures. None of these studies, however, have evaluated ethnicity and alcohol-metabolizing enzyme genotypes as covariates in their population pharmacokinetic modelling. We aimed to develop a population pharmacokinetic model using clinical and genetic factors and to identify covariates that influenced interindividual variability in alcohol clearance and volume of distribution. Hundred and eighty healthy subjects (90 Chinese and 90 Indians; 45 males and 45 females from each ethnic group) ingested a vodka-orange juice mixture to simulate social drinking. Subjects were genotyped for the ADH1B (Arg48His), ALDH2 (Glu504Lys) and CYP2E1 (c.-1293G>C and c.-1053C>T) polymorphisms. A base pharmacokinetic model was developed using the nonmem software (NONMEM Project Group, University of California, San Francisco, San Francisco, CA, USA) to determine the alcohol clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. Body weight and sex significantly influenced absorption rate and volume of distribution of alcohol. Body weight and ADH1B Arg48His polymorphism significantly influenced alcohol clearance. The Michaelis-Menten elimination rate (Vmax ) was decreased by 10% in homozygous ADH1B*1/*1 subjects. Ethnicity was not determined to be a significant covariate in the final population pharmacokinetic model. Gender and body weight were covariates that contributed most to explaining the observed interindividual alcohol pharmacokinetic variability. Of the four SNPs examined in this study, only ADH1B Arg48His polymorphism had a significant, though modest, effect on the pharmacokinetics of alcohol.

Expression Pattern, Ethanol‐Metabolizing Activities, and Cellular Localization of Alcohol and Aldehyde Dehydrogenases in Human Small Intestine

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol (EtOH). Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. This study aimed to systematically determine the functional expressions and cellular localization of ADH and ALDH family members in human small bowel. One hundred and seventeen surgical specimens of duodenal mucosae, 34 jejunal mucosal specimens, and 14 paired specimens of stomach, duodenum, and jejunum from same individuals were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing, and the ADH/ALDH activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies, and the cellular localizations were detected by immunohistochemistry and histochemistry. The activities of ADH1C*1/*1 allelotype were significantly higher than those of the ADH1C*1/*2 allelotype in duodenum (p<0.001) and in jejunum (p<0.05); and the activity of ADH2-expressing phenotype was significantly higher than that of the ADH2-missing phenotype in duodenum (p<0.05). The activities of ALDH2-inactive phenotype were not significantly different from those of the ALDH2-active phenotype in duodenum and jejunum. Stomach exhibited significantly lower ADH activity (p<0.05), and duodenum displayed significantly lower ALDH activity (p<0.001) comparing the paired gastric, duodenal, and jejunal mucosae of same individuals. Gender and age did not significantly influence the ADH and ALDH activities in duodenum. The isozyme protein contents in duodenum and jejunum were in the following decreasing order: ALDH1A1, ADH1/ALDH2, ADH3, ADH2, and ALDH3A1. Villous epithelial cells, cryptic Paneth cells, and Brunner's gland ductal cells revealed a greater immunostaining intensity with ADH1, ALDH1A1, and ALDH2. ADH and ALDH isozymes are differentially expressed in the various cell types of duodenum and jejunum. The results suggest that proximal small intestine can substantively contribute to first-pass metabolism of EtOH under certain conditions and that cytotoxic acetaldehyde and EtOH perturbation of retinol metabolism might play an etiological role in the pathogenesis of small bowel.

Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: A population‐based case–control study in China

Alcohol drinking is a major risk factor for esophageal cancer (EC) and the metabolism of ethanol has been suggested to play an important role in esophageal carcinogenesis. Epidemiologic studies, including genomewide association studies (GWAS), have identified single nucleotide polymorphisms (SNPs) in alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) to be associated with EC. Using a population-based case-control study with 858 EC cases and 1,081 controls conducted in Jiangsu Province, China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with EC in a Chinese population. Results showed that ADH1B (rs1229984) was associated with EC with odds ratios (ORs) of 1.34 [95% confidence interval (CI): 1.08-1.66] for G-allele carriers compared to A/A homozygotes. No heterogeneity was detected on this association across different strata of alcohol drinking and tobacco smoking. Statistical interaction between ALDH2 (rs671) and alcohol drinking on EC susceptibility in both additive and multiplicative scales was observed. Compared to G/G homozygotes, A-allele carriers were positively associated with EC among moderate/heavy drinkers (OR = 1.64, 95% CI: 1.12-2.40) and inversely associated with EC among never/light drinks (OR = 0.75, 95% CI: 0.54-1.03). In addition, statistical interaction between ALDH2 and ADH1B polymorphisms on EC susceptibility among never/light drinkers was indicated. We did not observe association of ADH1C polymorphism with EC. In conclusion, our findings indicated that ADH1B (rs1229984) was associated with EC independent of alcohol drinking and tobacco smoking status and alcohol drinking interacted with ALDH2 (rs671) on EC susceptibility in this high-risk Chinese population.

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.

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.

Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33 mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200 μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1 > ALDH2 > ADH3 ≈ ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.

Genetic Polymorphisms of Genes Coding to Alcohol‐Metabolizing Enzymes in Western Mexicans: Association of CYP2E1*c2/CYP2E1*5B Allele with Cirrhosis and Liver Function

Alcoholic cirrhosis constitutes a major public health problem in the world where ADH1B, ALDH2, and CYP2E1 polymorphisms could be playing an important role. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy control individuals (C) and patients with alcoholic cirrhosis (AC) from western Mexico. Ninety C and 41 patients with AC were studied. Genotype and allele frequency were determined through polymerase chain reaction-restriction fragment length polymorphisms. Polymorphic allele distribution in AC was 1.6%ADH1B*2, 0.0%ALDH2*2, and 19.5%CYP2E1*c2; in C: 6.1%ADH1B*2, 0%ALDH2*2, and 10.6%CYP2E1*c2. CYP2E1*c2 polymorphic allele and c1/c2 genotype frequency were significantly higher (p < 0.05 and p < 0.01, respectively) in patients with AC when compared to C. Patients with AC, carrying the CYP2E1*c2 allele, exhibited more decompensated liver functioning evaluated by total bilirubin and prothrombin time, than c1 allele carrying patients (p < 0.05). Cirrhosis severity, assessed by Child's Pugh score and mortality, was higher in patients carrying the c2 allele, although not statistically significant. In this study, CYP2E1*c2 allele was associated with susceptibility to AC; meanwhile, ADH1B*2 and ALDH2*2 alleles were not. CYP2E1*c2 allele was associated with AC severity, which could probably be attributed to the oxidative stress promoted by this polymorphic form. Further studies to clearly establish CYP2E1*c2 clinical relevance in the development of alcohol-induced liver damage and its usefulness as a probable prognostic marker, should be performed. Also, increasing the number of patients and including a control group conformed by alcoholic patients free of liver damage may render more conclusive results. These findings contribute to the understanding of the influence of gene variations in AC development among populations, alcohol metabolism, and pharmacogenetics.

Determination of the effects of Alcohol Dehydrogenase (ADH) 1B and ADH1C polymorphisms on alcohol dependence in Turkey

Alcoholism is a complex genetically influenced disorder which refers to alcohol abuse and alcohol dependence. There are controversial results on the role of gene polymorphisms in alcohol dependence in the literature. Differences in population groups and selective inclusion criteria for alcohol dependence may affect results. In this study, we investigated the role of ADH1B Arg48His (rs1229984) and, ADH1C Ile350Val (rs698) gene polymorphisms in Turkish population. 100 healthy volunteers and 75 patients who were admitted to Ege University Alcohol Dependence Unit enrolled in the study. We found significant increase both in ADH1B (Arg48His) polymorphism Arg allele and Arg/Arg genotype frequency in patients. No profound connection between alcohol dependence and ADH1C Ile350Val gene polymorphism was detected. Alcohol dependence is an important health problem that depends on many genetic and environmental factors but we think that it is possible to interpret genetic risk for developing early diagnostic methods and treatment strategies by comprehensive linkage and association studies.

ADH1B and ALDH2 polymorphisms and their associations with increased risk of squamous cell carcinoma of the head and neck in the Korean population

Alcohol consumption is a major risk factor for squamous cell carcinoma of the head and neck (SCCHN). Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are key enzymes in ethanol metabolism. The objective of this study was to investigate the relationships of ADH and ALDH single nucleotide polymorphisms (SNPs) with the risk of developing SCCHN in a Korean sample. We genotyped ADH1B +3170A>G (rs1229984) and ALDH2 +1951G>A (rs671) SNPs in 225 Korean SCCHN patients and 301 healthy controls by single base extension and TaqMan assay. The frequencies of the ADH1B +3170A>G (*2*2/*2*1/*1*1) genotypes were 48.0%/38.7%/13.3% in SCCHN patients, and 57.8%/37.2%/5.0% in controls, respectively. The odds ratio (OR) and 95% confidence interval of the ADH1B*1*1 genotype was 1.89 (1.23-2.92) relative to the *2*2 genotype. The frequencies of the ALDH2 +1951G>A (*1*1/*1*2/*2*2) genotypes were 67.6%/31.6%/0.9% in SCCHN patients, and 67.8%/29.6%/2.7% in controls, respectively. In subgroup analyses according to smoking and alcohol drinking status, the OR of the ADH1B*1*1 genotype was increased in the heavy drinker group [8.85 (1.095-40.0)] and in the heavy smoker group [4.7 (1.54-14.29)]. We conclude that the ADH1B*1*1 genotype is associated with an increased risk of SCCHN, especially in heavy drinkers and heavy smokers. This genotype could be a useful biomarker for identifying Koreans with a greater risk of SCCHN.