Association of metabolic gene polymorphisms with alcohol consumption in controls

The objectives were to study the association between metabolic genes involved in alcohol metabolism (CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1) and alcohol consumption in a large sample of healthy controls. Healthy subjects were selected from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Subjects with information on both alcohol consumption and at least one of the studied polymorphisms were included in the analysis (n=2224). Information on the amount of alcohol consumption was available for a subset of subjects (n=844). None of the studied genes was significantly associated with drinking habits. A significant heterogeneity with age was observed when studying the association between CYP2E1 RsaI and alcohol drinking. CYP2E1 RsaI polymorphism was significantly associated with being a never drinker at older ages (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-4.8; at ages above 68 years), while the association was reversed at ages below 47 years (OR 0.5, 95% CI 0.2-1.4). For subjects with detailed information on alcohol intake, no association between alcohol quantity and polymorphisms in metabolic genes was observed; subjects carrying the NQO1 polymorphism tended to drink more than subjects carrying the wild-type alleles. Therefore, no significant association between CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1 polymorphisms and alcohol consumption was observed in healthy controls.     

Association between metabolic gene polymorphisms and susceptibility to peripheral nerve damage in workers exposed to n-hexane: A preliminary study

Abstract

Chronic exposure to n-hexane may result in peripheral neuropathy. 2,5-Hexanedione (2,5-HD) has been identified as a toxic metabolite of n-hexane. The CYP2E1, CYP1A1 and GST genes are involved in the formation of 2,5-hexanedione from n-hexane as well as the elimination of 2,5-HD-formed electrophile, and these genes are highly polymorphic in the general population. A nested case-control study in an industrial cohort was conducted to evaluate the associations between polymorphisms in these metabolic genes and n-hexane-induced peripheral nerve damage. The study subjects included 22 cases, who worked in a printing factory with symptoms of peripheral nerve damage, and 163 controls, who came from the same factory of cases. DNA was extracted from blood samples and genotyping was conducted for CYP2E1 Pst, CYP2E1 Dra, CYP2E1 Ins96, CYP1A1 Msp, GSTT1 null, GSTM1 null and GSTP1 105V. Unconditional logistic regression was applied to estimate the odds ratio and 95% confidence intervals. There were no significant differences between the two groups regarding age, sex, smoking and alcohol status. A significant association between Dra polymorphism and peripheral nerve damage was found. The frequency of CYP2E1 Dra homozygous mutation in the case group (18.2%) was higher than that in the control group (3.7%, p=0.015). Individuals with homozygote genotype (CC) of CYP2E1 Dra had a significantly higher risk of peripheral nerve damage compared with those with DD genotype (adjusted OR?=?5.58, 95% CI?=?1.32–23.65) after n-hexane exposure duration, sex, age, smoking and alcohol status were adjusted. No significant association was found that CYP2E1 Pst, CYP2E1 Ins96, CYP1A1 Msp, GSTT1, GSTM1, GSTP gene polymorphisms associated with the susceptibility of peripheral nerve damage. These findings suggested that CYP2E1 gene might increase the susceptibility to n-hexane-induced peripheral damage.     

Effects of polymorphisms in alcohol metabolism and oxidative stress genes on survival from head and neck cancer

BackgroundHeavy alcohol consumption increases risk of developing squamous cell carcinoma of the head and neck (SCCHN). Alcohol metabolism to cytotoxic and mutagenic intermediates acetaldehyde and reactive oxygen species is critical for alcohol-drinking-associated carcinogenesis. We hypothesized that polymorphisms in alcohol metabolism-related and antioxidant genes influence SCCHN survival.MethodsInterview and genotyping data (64 polymorphisms in 12 genes) were obtained from 1227 white and African-American cases from the Carolina Head and Neck Cancer Epidemiology study, a population-based case–control study of SCCHN conducted in North Carolina from 2002 to 2006. Vital status, date and cause of death through 2009 were obtained from the National Death Index. Kaplan–Meier log-rank tests and adjusted hazard ratios were calculated to identify alleles associated with survival.ResultsMost tested SNPs were not associated with survival, with the exception of the minor alleles of rs3813865 and rs8192772 in CYP2E1. These were associated with poorer cancer-specific survival (HR_rs3813865, 95%CI = 2.00, 1.33–3.01; HR_rs8192772, 95%CI = 1.62, 1.17–2.23). Hazard ratios for 8 additional SNPs in CYP2E1, GPx2, SOD1, and SOD2, though not statistically significant, were suggestive of differences in allele hazards for all-cause and/or cancer death. No consistent associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT.ConclusionsWe identified some polymorphisms in alcohol and oxidative stress metabolism genes that influence survival in subjects with SCCHN. Previously unreported associations of SNPs in CYP2E1 warrant further investigation.     

Polymorphisms of alcohol metabolizing enzyme and cytochrome P4502E1 genes in mongolian population

Although the genetic polymorphism of the alcohol-metabolizing enzymes was extensively studied at the molecular level by many investigators, the genetic polymorphism studies for ethanolmetabolizing enzymes in Mongolians are very rare. The present study was therefore performed to determine the genetic distribution of various forms of alcohol-metabolizing enzymes such as alcohol dehydrogenase 2 (ADH2, currently accepted nomenclature ADH1B), ADH3 (ADH1C), aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1) in 300 healthy Mongolian males. Genetic polymorphisms were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The allele frequencies ofADH2 *1 andADH2 *2 were 0.24 and 0.76;ADH3 *1 andADH3 *2 were 0.92 and 0.08;ALDH2 *1 andALDH2 *2 were 0.96 and 0.04; andCYP2E1 *C andCYP2E1 *D were 0.15 and 0.85, respectively. Compared to the results reported by other investigators, the allele frequencies ofALDH2 *2 andCYP2E1 *C among Mongolian subjects were much lower than among East Asians (Korean, Japanese, and/or Han-Chinese), while those ofADH2 andADH3 were more similar. Interestingly, this study shows that the ineffectiveALDH2 gene (ALDH2*2 allele) among Mongolians is not as common as among East Asians.     

Association of genetic polymorphisms of alcohol-metabolizing enzymes with excessive alcohol consumption in Japanese men

To evaluate the independent and interactive contributions of alcohol dehydrogenase-2 (ADH2), aldehyde dehydrogenase-2 (ALDH2) and ethanol-induced isozyme cytochrome P450-2E1 (CYP2E1) genes to alcohol consumption large enough to induce health problems, 643 healthy Japanese men aged between 23 and 64 years, recruited from two different occupational groups, were analyzed for genotype and drinking habits. The frequency of excessive alcohol consumers (EAC) who drank 90 ml or more alcohol more than 3 days a week was significantly higher in subjects possessing the ALDH2(1)/ALDH2(1) genotype than in those having ALDH2(1)/ALDH2(2) or ALDH2(2)/ALDH2(2) genotypes. A significant difference was also found in the different genotypes of CYP2E1. Moreover, a borderline significant interaction between the ALDH2 and CYP2E1 genotypes on excessive alcohol consumption was observed, i.e., the group of subjects having the c2 allele of CYP2E1 had a higher frequency of EAC than those having c1/c1 genotypes in the genotype subgroup ALDH2(1)/ALDH2(1), whereas these were not found in the heterozygote and homozygote subgroups of the ALDH2(2) allele. Neither the independent nor interactive genetic effect of ADH2 on excessive alcohol consumption was obvious. In conclusion, Japanese men with the ALDH2(1)/ALDH2(1) genotype and the c2 allele of CYP2E1 are at higher risk of showing excessive alcohol consumption.     

Association analysis of gene polymorphism in alcohol metabolizing enzymes with risk for coronary atherosclerosis

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5'-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B (*G (+MslI) allele), CYP2E1 (**C2 (+PstI) allele) and CYP2E1 (*C (-Dra I)2 allele) were 8.48 +/- 1.86%; 1.20 +/- 0.69% and 10.00 +/- 1.90%, respectively. The 2ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7*C (-Sty I) allele was 44.58 +/- 3.21%. A significantly higher frequency of CYP2E1 (*C2 (+Pst I)) allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03-20.01). The tendency to significant effect of A1A2 genotype in ADH1B Msl 1 polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0,042) were also revealed. Association of A1A2 genotype in ADHIB Msl I polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.     

CYP1A1, GSTM1 and GSTT1 polymorphisms and lung cancer: a pooled analysis of gene–gene interactions

Gene–environment interactions have been extensively studied in lung cancer. It is likely that several genetic polymorphisms cooperate in increasing the individual risk. Therefore, the study of gene–gene interactions might be important to identify high-susceptibility subgroups. GSEC is an initiative aimed at collecting available data sets on metabolic polymorphisms and the risks of cancer at several sites and performing pooled analyses of the original data. Authors of published papers have provided original data sets. The present paper refers to gene–gene interactions in lung cancer and considers three polymorphisms in three metabolic genes: CYP1A1, GSTM1 and GSTT1. The present analyses compare the gene–gene interactions of the CYP1A1*2A, GSTM1 and GSTT1 polymorphisms from studies on lung cancer conducted in Europe and the USA between 1991 and 2000. Only Caucasians have been included. The data set includes 1466 cases and 1488 controls. The only clear-cut association was found with CYP1A1*2A. This association remained unchanged after stratification by polymorphisms in other genes (with an odds ratio [OR] of approximately 2.5), except when interaction with GSTM1 was considered. When the OR for CYP1A1*2A was stratified according to the GSTM1 genotype, the OR was increased only among the subjects who had the null (homozygous deletion) GSTM1 genotype (OR=2.8, 95% CI=0.9–8.4). The odds ratio for the interactive term (CYP1A1*2A by GSTM1) in logistic regression was 2.7 (95% CI=0.5–15.3). An association between lung cancer and the homozygous CYP1A1*2A genotype is confirmed. An apparent and biologically plausible interaction is suggested between this genotype and GSTM1.     

Polymorphisms of the CYP1A1 and CYP2E1 genes in head and neck squamous cell carcinoma risk

Polymorphisms in genes that encode P450 cytochrome enzymes may increase carcinogen activation or decrease their inactivation and consequently, promote the development of cancer. The aims of this study were to identify the MspI-CYP1A1, PstI-CYP2E1 and DraI-CYP2E1 polymorphisms in patients with head and neck cancer and to compare with individuals without cancer; to evaluate the association of these polymorphisms with risk factors and clinical histopathological parameters. In the study group, 313 patients were evaluated for CYP1A1, 217 for CYP2E1 (PstI) and 211 for CYP2E1 (DraI) and in the control group 417, 334 and 374 individuals, respectively. Molecular analysis was performed by PCR–RFLP technique, and chi-square and multiple logistic regression tests were used for statistical analysis. The result of analysis regarding individuals evaluated for CYP1A1 (MspI) showed that age (OR: 8.15; 95% CI 5.57–11.92) and smoking (OR: 5.37; 95% CI 3.52–8.21) were predictors for the disease; for the CYP2E1 (PstI and DraI), there were associations with age (PstI-OR: 9.10; 95% CI 5.86–14.14/DraI-OR: 8.07; 95% CI 5.12–12.72), smoking (PstI-OR: 4.10; 95% CI 2.44–6.89/DraI-OR: 5.73; 95% CI 3.34–9.82), alcohol (PstI-OR: 1.93; 95% CI 1.18–3.16/DraI-OR: 1.69; 95% CI 1.02–2.81), respectively, with disease development. CYP2E1 (PstI) was less frequent in patient group (OR: 0.48; 95% CI 0.23–0.98). Regarding clinical histopathological parameters, CYP1A1 polymorphism was less frequent in the larynx primary anatomic site (OR = 0.45; 95% CI = 0.28–0.73; P = 0.014). In conclusion, we confirm that age, smoking and alcohol consumption are risk factors for this disease and the polymorphisms investigated have no association with the development of head and neck cancer.     

Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colorectal cancer

Colorectal cancer (CRC) is one of the most common forms of cancer in Western countries. CRC has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. Therefore, we determined whether polymorphisms in the genes coding for microsomal epoxide hydrolase (EPHX1), NAD(P)H:quinone oxidoreductase (NQO1), cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase (ADH3) predispose to the development of CRC. DNA samples were obtained from 371 patients with sporadic CRC and 415 healthy controls. Patients and controls were all of Caucasian origin. All genetic polymorphisms were determined by polymerase chain reaction, eventually followed by restriction-fragment-length-polymorphism analyses, except for the EPHX1 codon 113 polymorphism, which was genotyped by an allele-specific discrimination assay. Calculation of crude Odds Ratios (ORs) revealed an increased risk for CRC associated with variant NQO1 (OR 1.5, 95% CI 1.1-2.0) and CYP2E1 intron 6 genotypes (OR 2.2, 95% CI 1.3-3.8). However, after adjustment for age and gender, logistic regression analyses only showed a statistically significant risk for CRC associated with variant NQO1 genotypes (OR 1.6, 95% CI 1.03-2.4). No associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, these data suggest that the presence of variant NQO1 genotypes, with expected reduced enzyme activities might enhance susceptibility to CRC.     

Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes

Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH), cytochrome p4502E1 (CYP2E1) and catalase. This metabolite is then detoxified by aldehyde dehydrogenase 2 (ALDH2), a key enzyme in the elimination of acetaldehyde, via further oxidation to acetic acid. The toxic effects of acetaldehyde are well documented and may be partially mediated by genotoxic damage. In the present study, we investigated the effects of alcohol-drinking behavior and genetic polymorphisms in two different genes (ALDH2 and CYP2E1) on the micronuclei (MN) frequency in 248 healthy Japanese men. Genotyping was performed by PCR-RFLP analysis. The ALDH2 variant (deficient type) was significantly associated with an increased MN frequency in subjects drinking more than three times/wk, while habitual drinkers with wild-type CYP2E1 also had a significantly increased MN frequency. Furthermore, when the subjects were divided into eight groups according to their drinking frequency and genotypes of ALDH2 and CYP2E1, we found that habitual drinkers with homozygous CYP2E1*1/*1 and heterozygous ALDH2*1/*2 or homozygous ALDH2*2/*2 showed the highest mean MN frequency. In the present study, we found clear associations among ALDH2 and CYP2E1 gene polymorphisms, alcohol-drinking behavior and genotoxic effects in a healthy Japanese population. Therefore, analysis of the polymorphisms of alcohol-metabolizing enzymes may lead to elucidation of the mechanism(s) for individual susceptibilities to the toxicity of ethanol metabolites.     

Polymorphism of metabolic genes and susceptibility to occupational chronic manganism

In this study we investigated genetic polymorphisms of five metabolizing genes and their association with occupational chronic manganism. We recruited 49 patients with chronic manganism and 50 unrelated healthy control subjects who were welders and ferromanganese smelters and occupationally exposed to manganese dust and fume in the same workshops from three metallurgical industries. The controls were matched to the cases by sex, age, cigarette and alcohol intake, as well as the manganese exposure duration. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the cytochrome P450 2D6L gene (CYP2D6L) and the NAD(P)H:quinone oxidoreductase gene (NQO1). Allele-specific PCR was used to detect the cytochrome P450 1A1 gene (CYP1A1), and the glutathione-S-transferase mu and theta genes (GSTM and GSTT). The frequency of polymorphic alleles, a mutation of CYP2D6L, was significantly lower in patients with chronic manganism (16.3%) than in controls (29.0%). Individuals with the homozygote polymorphism (L/L) of CYP2D6 had a 90% decreased risk of chronic manganism compared with the wild-type (Wt/Wt) (odds ratio =0.10, 95% confidence interval = 0.01-0.82). A significant association between the CYP2D6 genotype subgroup and the latency of chronic manganese poisoning was also found. Patients who had homozygous (L/L) or heterozygous (Wt/L) mutant alleles developed manganism an average of 10 years later than those who were homozygous wildtype (Wt/Wt). However, the allele and genotype frequencies of CYP1A1 and NQO1 genes were distributed similarly in cases and controls. In addition, no difference in the frequencies of GSTM1 and GSTT1 null genotypes were observed between cases and controls. The results suggest that CYP2D6L gene polymorphism might influence susceptibility to manganese-induced neurotoxicity. However, because of limited sample size, our results should be validated in large-scale studies.     

An estimate of polymorphism of ADH1B,ALDH2, and CYP2E1 alcohol biotransformation genes in Siberian indigenous and immigrant populations

In the present article, the polymorphism of ADH1B, ALDH2, and CYP2E1 genes is studied in populations of Shors, Russians of Siberia, and progenies of mixed Russian-Shor marriages. Reliable differences between groups according to the frequency of ADH1B, ALDH2, and CYP2E1 genotypes and alleles are revealed. The article shows the high heterozygosis levels of the ADH1B and ALDH2 genes. Gene distances prove that mongrels and Shors are very close to each other (d = 0.005) and Russians of Siberia are not similar to the Russians of the Central Russia (d = 0.046).     

Formation of acetaldehyde-derived DNA adducts due to alcohol exposure

Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for cancers of the upper aerodigestive tract, including the oral cavity, pharynx, larynx and esophagus, and for cancer of the liver. Ingested ethanol is mainly oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1), and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate. Polymorphisms of the genes which encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity. ADH1B*2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B*1 allele. Otherwise, approximately 40% of Japanese have single nucleotide polymorphisms (SNPs) of the ALDH2 gene. The ALDH2 *2 allele encodes a protein with an amino acid change from glutamate to lysine (derived from the ALDH2*1 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/*2) nor heterozygote (ALDH2*1/*2) is able to metabolize acetaldehyde promptly. Acetaldehyde is a genotoxic compound that reacts with DNA to form primarily a Schiff base N²-ethylidene-2′-deoxyguanosine (N²-ethylidene-dG) adduct, which may be converted by reducing agents to N²-ethyl-2′-deoxyguanosine (N²-ethyl-dG) in vivo, and strongly blocked translesion DNA synthesis. Several studies have demonstrated a relationship between ALDH2 genotypes and the development of certain types of cancer. On the other hand, the drinking of alcohol induces the expression of CYP2E1, resulting in an increase in reactive oxygen species (ROS) and oxidative DNA damage. This review covers the combined effects of alcohol and ALDH2 polymorphisms on cancer risk. Studies show that ALDH2*1/*2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH2*1/*1 homozygotes. Moreover, they support that chronic alcohol consumption contributes to formation of various DNA adducts. Although some DNA adducts formation is demonstrated to be an initiation step of carcinogenesis, it is still unclear that whether these alcohol-related DNA adducts are true factors or initiators of cancer. Future studies are needed to better characterize and to validate the roles of these DNA adducts in human study.     

Allelic variation at alcohol metabolism genes (<Emphasis Type="Italic">ADH1B</Emphasis>,<Emphasis Type="Italic"> ADH1C</Emphasis>,<Emphasis Type="Italic"> ALDH2</Emphasis>) and alcohol dependence in an American Indian population

Enzymes encoded by two gene families, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B (previously ADH2), ADH1C (previously ADH3), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe (n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study.     

Polymorphisms in Alcohol Metabolism Genes ADH1B and ALDH2, Alcohol Consumption and Colorectal Cancer

Background

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population.

Methodology/Principal Findings

SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption.

Conclusions/Significance

Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.     

Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients

The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene–environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.     

Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms

Ethanol is almost totally broken down by oxidative metabolism in vivo. Ethanol per se is considered to be neither carcinogenic, mutagenic nor genotoxic. However, during the metabolic conversion of ethanol to acetaldehyde and acetate, the organism is exposed to both ethanol and acetaldehyde and therefore ethanol is suspected to be co-carcinogenic. The genetic polymorphisms of alcohol dehydrogenase-2 (ADH1B) and acetaldehyde dehydrogenase-2 (ALDH2) influence the metabolism of alcohol. The ADH1B*1/*1 genotype encodes the low-activity form of ADH1B, and ALDH2*1/*2 and ALDH2*2/*2 genotype encode inactive ALDH2. The aim of this study was to test the hypothesis that polymorphisms of the ADH1B and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biomarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men. There was a significant trend for the mean micronuclei (MN) frequency in habitual or moderate drinkers without a smoking habit to increase as the numbers of the *1 allele in ADH1B increased (P=0.039 or P=0.029) and the *2 allele in ALDH2 increased (P=0.019 or P=0.037). A logistic regression analysis showed that the number of subjects with MN frequency levels more than median value of MN (3.0) was significantly higher in the subjects with the ADH1B*1 allele as adjusted estimates (OR 2.08, 95% C.I. 1.24-3.48), when the OR for the subjects with the ADH1B*2/*2 genotype was defined as 1.00. The number of subjects with MN frequency levels more than median value of MN was also significantly higher in the subjects with the ALDH2*2 allele as adjusted estimates (OR 1.79, 95% C.I. 1.04-3.11), when the OR for the subjects with the ALDH2*1/*1 genotype was defined as 1.00. The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers.     

Alcohol and aldehyde dehydrogenase polymorphisms and risk for suicide: a preliminary observation in the Japanese male population

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop suicidal behavior. Genetic factors for suicidal behavior have been observed in family, twin, and adoption studies. Because alcohol dehydrogenase (ADH1B) His47Arg and mitochondrial aldehyde dehydrogenase (ALDH2) Glu487Lys single nucleotide polymorphisms (SNPs), which affect alcohol metabolism, have been reported to exert significant impacts on alcohol consumption and on the risk for alcoholism in East Asia populations, we explored associations of the two functional SNPs with suicide using a case–control study of 283 completed suicides and 319 control subjects in the Japanese population. We found that the inactive ALDH2 allele (487Lys) was significantly less frequent in the completed suicides (19.3%) than in the controls (29.3%), especially in males, whereas this was not the case in females. The males bearing alcoholism‐susceptible homozygotes at both loci (inactive ADH1B Arg/Arg and active ALDH2 Glu/Glu genotypes) have a 10 times greater risk for suicide compared with the males bearing alcoholism‐protective homozygotes at both loci. Our data show the genetic impact of the two polymorphisms on suicidal behavior in the Japanese population, especially in males. Because we did not verify the daily alcohol consumption, the association of these SNPs with suicide might be due to alcoholism itself. Further studies using case–control subjects, which verifies the details of current and past alcohol consumption and diagnosis for alcoholism, are required to confirm these findings.     

Association analysis of alcohol metabolizing enzymes <Emphasis Type="Italic">ADH1B,ADH7, CYP2E1</Emphasis> gene polymorphism with risk for coronary atherosclerosis

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5′-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B ^* G (+MslI) allele, CYP2E1 ^* C2 (+PstI) allele and CYP2E1 ^* C (-DraI) allele were 8.48 ± 1.86, 1.20 ± 0.69, and 10.00 ± 1.90%, respectively. The ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7 ^* C (-StyI) allele was 44.58 ± 3.21%. A significantly higher frequency of CYP2E1 PstI C2 allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03–20.01). The tendency to significant effect of A1A2 genotype in ADH1B MslI polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0.042) were also revealed. Association of A1A2 genotype in ADH1B MslI polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.     

Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort

The association is still not clear between the common APOE polymorphism and coronary heart disease (CHD) risk, nor its modulation by diet. Thus, our aim was to study the association between the APOE genotypes and incident CHD and how dietary fat and alcohol consumption modify these effects. We performed a nested case-control study in the Spanish European Prospective Investigation into Cancer and Nutrition cohort. Healthy men and women (41?440, 30-69 years) were followed up over a 10-year period, with the incident CHD cases being identified. We analyzed 534 incident CHD cases and 1123 controls. APOE, dietary intake and plasma lipids were determined at baseline. The APOE polymorphism was significantly associated with low-density lipoprotein cholesterol (LDL-C), and gene-alcohol interactions in determining LDL-C were detected. In the whole population, the E2 allele was significantly associated with a lower CHD risk than E3/E3 subjects [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.38-0.89]. The E4 allele did not reach statistical significance vs. E3/E3 (OR, 1.17; 95% CI, 0.88-1.58). However, saturated fat intake modified the effect of the APOE polymorphism in determining CHD risk. When saturated fat intake was low (<10% of energy), no statistically significant association between the APOE polymorphism and CHD risk was observed (P=.682). However, with higher intake (≥10%), the polymorphism was significant (P=.005), and the differences between E2 and E4 carriers were magnified (OR for E4 vs. E2, 3.33; 95% CI, 1.61-6.90). Alcohol consumption also modified the effect of the APOE on CHD risk.In conclusion, in this Mediterranean population, the E2 allele is associated with lower CHD risk, and this association is modulated by saturated fat and alcohol consumption.