Relevance of Both Daily Hassles and the ALDH2 Genotype to Problem Drinking among Japanese Male Workers

The effects of genetic polymorphisms in the ALDH2 and ADH2 genes and stress levels, as assessed by the daily hassles scale on the prevalence of problem drinkers, were investigated in males in a Japanese occupational population. The frequency of problem drinkers was estimated by the Kurihama Alcoholism Screening Test (KAST). The prevalence of those with a high KAST score (≥0.0) was significantly higher in ALDH2*1/*1 (18.4%) than in ALDH2*1/*2 (4.8%). Multiple logistic regression analysis revealed significant contributions by levels of alcohol consumption, the ALDH2 genotype, and daily hassles to the prevalence of those with a high KAST score. When we analyzed the data for each ALDH2 genotype, heavier alcohol consumption (≥28.8 ml/day), older age (≥40 years old), and very high daily hassles levels (≥20) significantly increased the prevalence of problem drinkers in ALDH2*1/*1. On the contrary, no variables other than heavier alcohol consumption influenced the prevalence in ALDH2*1/*2. In summary, the present study revealed significant contributions of both daily hassles and the ALDH2 genotype to the increase of problem drinkers in an occupational population. Health promotion activities to prevent from alcohol dependence should focus on ALDH2*1/*1 , especially those of middle age, and should include stress management as a part of their activities.     

Kimchi and soybean pastes are risk factors of gastric cancer

AIM: This case-control study investigated the effects of kimchi,soybean paste, fresh vegetables,nonfermented alliums, nonfermented seafood, nonfermented soybean foods, and the genetic polymorphisms of some metabolic enzymes on the risk of gastric cancer in Koreans. METHODS: We studied 421 gastric cancer patients and 632 age- and sex-matched controls. Subjects completed a structured questionnaire regarding their food intake pattern. Polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase mu 1 (GSTM1),glutathione S-transferase theta 1 (65777) and aldehyde dehydrogenase 2 (ALDH2) were investigated. RESULTS: A decreased risk of gastric cancer was noted among people with high consumption of nonfermented alliums and nonfermented seafood. On the other hand, consumption of kimchi, and soybean pastes was associated with increased risk of gastric cancer. Individuals with the CYP1A1 Ile/Val or Val/Val genotype showed a significantly increased risk for gastric cancer. Increased intake of kimchi or soybean pastes was a significant risk factor for the CYP1A1 lie/lie, the CYP2E1 c1/c1,the GSTM1 non-null, the GSTT1 non-null, or the ALDH2 *1/*1 genotype.In addition, eating soybean pastes was associated with the increased risk of gastric cancer in individuals with the GSTM1 null type. Nonfermented alliums were significant in individuals with the CYP1A1 lie/lie, the CYP2E1 c1/c2 or c2/c2, the GSTT1 null, the GSTT1 non-null, or the ALDH2 *1/*2 or *2/*2 genotype,nonfermented seafood was those with the CYP1A1 lie/lie,the CYP2E1 c1/c1, the ALDH2 *1/*1 genotype or any type of GSTM1 or GSTT1. In homogeneity tests, the odds ratios of eating kimchi for gastric cancer according to the GSTM1 or 65777 genotype were not homogeneous. CONCLUSION: Kimchi, soybean pastes, and the CYP1A1 Ile/Val or Val/Val are risk factors,and nonfermented seafood and alliums are protective factors against gastric cancer in Koreans. Salt or some chemicals contained in kimchi and soybean pastes, which are increased by fermentation,would play important roles in the carcinogenesis of stomach cancer.Polymorphisms of the CYP1A1, CYP2E1, GSTM1, GSTT1, and ALDH2 genes could modify the effects of some environmental factors on the risk of gastric cancer.     

Alcohol-metabolizing enzyme gene polymorphisms and alcohol chronic pancreatitis among Polish individuals

Background and aims. Chronic pancreatitis develops in 5–10% of alcohol addicts. In developed societies, alcohol is the cause of chronic pancreatitis in at least 70–80% of cases. The genetic polymorphism of enzymes involved in alcohol metabolism is relevant in the etiopathogenesis of chronic pancreatitis. The aim of the study was to find the ADH, ALDH2 and CYP2E1 alleles and genotypes in the Polish population that are likely to be responsible for higher susceptibility to chronic alcohol pancreatitis. Material and methods. We determined the allele and genotype of ADH2, ADH3, ALDH2 and CYP2E1 in 141 subjects: 44 with alcohol chronic pancreatitis (ACP), 43 healthy alcoholics and 54 healthy non-drinkers as the controls. Genotyping was performed using PCR-RELP methods on white cell DNA. Results. ADH2*1, ADH3*1 alleles and ADH2*1/*1, ADH3*1/*1 genotypes were statistically more frequent among the patients with ACP than among the controls. The ADH3*2/*2 genotype was more frequent among “healthy alcoholics” and in the controls than among those with ACP. In the studied group, only the ALDH2*1 allele was detected, all patients were ALDH2*1/*1 homozygotic. Differences in the CYP2E1 allele and genotype distribution in the examined groups were not significant. Conclusion. In the Polish population examined, ADH3*1 and ADH2*1 alleles may be risk factors for the development of alcoholism. The ADH3*2/*2 genotype may confer protection against ACP. CYP2E1 gene polymorphism is not related to alcoholism and ACP. The Polish population examined is ALDH2*1/*1 homozygotic.     

Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China

AIM＂ TO evaluate the impact of alcohol dehydrogenase 2 （ADH2） and aldehyde dehydrogenase 2 （ALDH2） polymorphisms on esophageal cancer risk. METHODS;One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2 genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer （PCR-CTPP） method. Unconditional logistic regression was used to calculate the odds ratios （OR） and 95% confidence interval （95% CI）. RESULTS; Both ADH2＊1 allele and ALDH2＊1/＊2 allele showed an increased risk of developing esophageal cancer. The adjusted OR （95% CI） for ADH2＊1 allele compared with ADH2＊2/＊2 was 1.65 （95% CI = 1.02-2.68） and 1.67 （95% CI = 1.02-2.72） for ALDH2＊1/＊2 compared with ALDH2＊1/＊1. A significant interaction between ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83 （95% CI = 1.13-2.95）. Furthermore, when compared with ADH2＊2/＊2 and ALDH2＊1/＊1 carriers, ADH2＊1 and ALDH2＊2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers     

Relationships of early esophageal cancer with human papillomavirus and alcohol metabolism

BACKGROUND It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2(ALDH2) is an important risk factor for the development of esophageal squamous cell carcinoma(ESCC). It remains controversial whether human papillomavirus(HPV) infection contributes to the occurrence/development of ESCC. There has been no study in which the relationship between ESCC and HPV in addition to alcohol dehydrogenase-1 B(ADH1 B) and ALDH2 genotypes was evaluated.AIM To evaluate relationships between HPV infection and development of esophageal cancer, particularly early esophageal cancer, based on ADH1 B/ALDH2 polymorphisms.METHODS We conducted an exploratory retrospective study using new specimens, and weenrolled 145 patients who underwent endoscopic resection for superficial ESCC and had been observed for more than two years by both physical examination and endoscopic examination in Hokkaido University Hospital. Saliva was collected to analyze genetic polymorphisms of ADH1 B/ALDH2. We performed in situ hybridization for resected specimens to detect HPV by using an HPV type 16/18 probe.RESULTS HPV was detected in 15(10.3%) of the 145 patients with ESCC. HPV-positive rates in inactive ALDH2*1/*2 and ALDH2*1/*1 + *2/*2 were 10.8% and 9.8%, respectively(P = 1.00). HPV-positive rates in slow-metabolizing ADH1 B*1/*1 and ADH1 B*1/*2 + *2/*2 were 12.0% and 10.0%, respectively(P = 0.72). HPV-positive rates in the heavy or moderate alcohol consumption group and the light or rare consumption group were 11.1% and 8.7%, respectively(P = 0.68). HPV-positive rates in the heavy smoking group and the light or no smoking group were 11.8% and 8.3%, respectively(P = 0.59). The 3-year incidence rates of secondary ESCC or head and neck cancer after initial treatment in the HPV-positive and HPVnegative groups were 14.4% and 21.4%(P = 0.22), respectively.CONCLUSION In the present situation, HPV status is considered to be less important than other risk factors, such as alcohol consumption, smoking habit, ADH1 B/ALDH2 polymorphisms, and HPV status would therefore have no effect on ESCC risk management.     

Self-Reported Alcohol-Associated Symptoms and Drinking Behavior in Three ALDH2 Genotypes Among Japanese University Students

BACKGROUND: Alcohol abuse is one of the most serious health problems among young adults. Nearly half of the Japanese population is sensitive to alcohol due to a genetic polymorphism in low K(m) aldehyde dehydrogenase (ALDH2). In the present study, we investigated the effects of the ALDH2 genotype on both self-reported alcohol-associated symptoms and alcohol drinking behavior among Japanese university students. METHODS: The study subjects were 423 (389 males and 34 females) university students in a medical university. The subjects completed a questionnaire regarding self-reported alcohol-associated symptoms and alcohol drinking behavior. The ALDH2 genotype was determined through digestion of polymerase chain reaction (PCR) products by a restriction enzyme Ksp632I. The frequency of alcohol-associated symptoms generally increased in the order ALDH2*1/*1, ALDH2*1/*2, ALDH2*2/*2 among males. The frequency of those who drink > or = 5 days/week was less than 10% in all genotype groups. However, the frequency of those who drink 1-4 days/week was significantly higher in ALDH2*1/*1 than that in ALDH2*1/*2 and in ALDH2*2/*2. A similar tendency also was observed in females. Mean amounts of alcohol consumption per occasion in the three ALDH2 genotypes stratified by drinking frequency generally increased significantly in the order ALDH2*2/*2, ALDH2*1/*2, ALDH2*1/*1 in both sexes. The proportion of binge drinkers defined by those who drink ethanol of > or = 75 ml per occasion on average also increased in the order ALDH2*2/*2 (0.0%), ALDH2*1/*2 (9.8%), ALDH2*1/*1 (22.1%) among male drinkers (> or = 1 day/month). CONCLUSIONS: We for the first time demonstrated clear associations between the ALDH2 genotype, self-reported alcohol-associated symptoms, and alcohol drinking behavior among Japanese university students.     

Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels

Moderate drinkers with a defective alcohol dehydrogenase type 3 (ADH3) genotype have higher high-density lipoprotein (HDL) levels and a decreased risk of coronary artery disease (CAD). We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan. The ALDH2 genotype of each subject was determined by polymerase chain reaction (PCR) analysis. HDL was adjusted for the alcohol intake, age, body mass index, smoking status, total cholesterol, triglycerides and HbA1c levels. None of the subjects had a history or ECG suggestive of CAD. The proportions of ALDH2, *1/*1, *1/*2, and *2/*2 (defective homozygote) were 45.8, 46.0, and 8.2%, respectively, for men. Drinking more than two drinks daily was associated with lower HDL levels in men with the defective genotypes compared with men with a normal genotype (55.6+/-0.9 vs. 51.2+/-0.9 mg/dl, mean+/-S.E., P<0.0001). Also, drinking more than 0.5 drinks daily was not associated with beneficial effects on HDL levels in women with defective ALDH2 genotypes. CONCLUSIONS: Alcohol intake did not have beneficial effects on HDL levels in the defective ALDH2 genotype and may not protect against CAD in subjects with defective ALDH2 genotypes.     

Genetic differences in ethanol metabolizing enzymes and blood pressure in Japanese alcohol consumers

Orientals have unique genetic polymorphisms in ethanol metabolizing enzymes, such as alcohol dehydrogenase-2 (ADH2), aldehyde dehydrogenase-2 (ALDH2) and cytochrome P450-2E1 (CYP2E1). Of the three studies conducted to clarify the influence of ALDH2 genotypes on sensitivity to the pressor effects of alcohol in Japanese, only one was suggested, though indirectly, higher sensitivity in drinkers having the genotype of inactive ALDH2. This discrepancy prompted us to determine ADH2, ALDH2 and CYP2E1 genotypes in the genomic DNA extracted from white blood cells of 855 healthy middle-aged Japanese men, and to analyse the associations with the alcohol-blood pressure (BP) relationship. No marked differences were found in the relationship among the genotypes of ALDH2, although the subjects with intact ALDH2 showed a slightly higher BP than those with inactive ALDH2 probably due to under-reporting of alcohol consumption in those with intact ALDH2 who could thus drink more. No significant influence of ADH2 genotypes was observed. A higher BP was noted in large volume alcohol consumers having c2/c2 genotype of CYP2E1. Multivariate regression analysis adjusting for the effects of age, body mass index and the volume of alcohol consumed, all of which are strong determinants of BP levels, showed only a marginal effect of c2 allele of CYP2E1 on diastolic BP elevations with increases in alcohol consumption. Thus it is concluded that the genetic polymorphisms in ethanol-metabolizing enzymes do not greatly influence the alcohol-BP relationship in Japanese men.     

Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males

AIM: To investigate the association between the genetic polymorphisms of ADH2 and ALDH2, lifetime alcohol consumption and esophageal cancer risk in the Taiwanese men. METHODS: Between August 2000 and June 2003, 134 pathologically-proven esophageal squamous cell carcinoma male patients and 237 male controls were recruited from Kaohsiung Medical University Hospital and Kaohsiung Veterans General Hospital in southern Taiwan. ADH2 and ALDH2 polymorphisms were genotyped using PCR-RFLP. RESULTS: Compared to those with ADH2*2/*2, individuals with ADH2*l/*2 and ADH2*1/*1 had 2.28-and 7.14-fold, respectively, increased risk of developing esophageal cancer (95%CI = 1.11-4.68 and 2.76-18.46) after adjusting for alcohol consumption and other covariates. The significant increased risk was also noted among subjects with ALDH2*l/*2 (adjusted OR (AOR) = 5.25, 95%CI = 2.47-11.19), when compared to those with ALDH2*1/*1. The increased risk of esophageal cancer was made greater, when subjects carried both ADH2*1/*1 and ALDH2*1/*2, compared to those with ADH2*1/*2 or ADH2*2/*2 and ALDH2*1/*1 (AOR = 36.79, 95%CI = 9.36-144.65). Furthermore, we found a multiplicative effect of lifetime alcoholic consumption and genotypes (ADH2 and ALDH2) on esophageal cancer risk. CONCLUSION: Our findings suggest that polymorphisms of ADH2 and ALDH2 can modify the influence of alcoholic consumption on esophageal cancer risk.     

乙醛脱氢酶2基因多态性与酒精性肝病患者饮酒特点和疾病发生的关系*

目的 分析乙醛脱氢酶2（ALDH2）基因多态性与酒精性肝病（ALD）患者饮酒特点与疾病发生的关系。方法 采用TaqMan荧光定量PCR法,对无血缘关系的296例健康对照者（HC）以及221例ALD患者进行ALDH2基因多态性检测,并分析其与ALD患者饮酒特征和疾病发生的关系。结果 ALDH2在健康人中突变频率为31.1%（92/296）,远高于欧美、非洲等国家（几乎为零）,稍高于亚洲平均水平（22%）;ALDH2*1/*1基因型频率,ALD患者组明显高于健康人[93.7%（207/221） Vs 69.0%（204/296）,OR=6.668,P<0.0001],ALDH2*1等位基因的频率,ALD患者组亦明显高于健康人[96.8%（428/442） Vs 82.9% （491/592）,OR=6.289,P<0.0001];ALDH2*1/*2基因型频率,ALD患者组明显低于健康人[6.3% （14/221） Vs 28.0% （83/296）,OR=0.174,P<0.0001],ALDH2*2/*2基因型频率,ALD患者组亦明显低于健康人[0% （0/221） Vs 3.0% （9/296）,OR=0.13,P<0.05]。ALDH2*2等位基因频率,ALD患者组亦明显低于健康人[3.2% （14/442） Vs 17.1% （101/592）,OR=0.159,P<0.01];ALDH2基因多态性在ALD患者疾病进程的各个阶段分布无明显统计学差异;与ALDH2*1/*1基因型相比,拥有ALDH2*2 携带者基因型饮酒者在较少的总饮酒量情况下即可发生ALD（P均<0.05）。结论 ALDH2*1等位基因是饮酒者发生ALD的重要危险因素,在较多饮酒量和较长时间饮酒的情况下才发生ALD;ALDH2*2等位基因可“保护”机体避免发生ALD,但饮酒者在较少饮酒量和较短饮酒时间的情况下即可发生ALD。     

Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis

BACKGROUND AND AIM: Susceptibility to organ damage induced by alcohol may be due to inherited variation (polymorphism) in ethanol-metabolizing enzymes, or to polymorphisms affecting free radical or lipid metabolism mediated by enzymes such as glutathione S-transferases and apolipoprotein E. The aim was to compare the genotype frequencies of alcohol dehydrogenase-2 (ADH2), ADH3, aldehyde dehydrogenase-2 (ALDH2), cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and apolipoprotein E in patients with alcoholic cirrhosis and alcoholic chronic pancreatitis to those in control groups. PATIENTS AND METHODS: The case-control study was restricted to Caucasian adults: 57 with alcoholic cirrhosis, 71 with alcoholic chronic pancreatitis, 57 alcoholics without apparent organ damage and 200 healthy blood donors. Genotypes were determined by restriction fragment length polymorphism after amplification of genomic DNA by polymerase chain reaction. RESULTS: The genotype ADH3*2/*2 was more frequent in patients with cirrhosis (40%) than blood donors (12%; OR 4.92, 95% CI 2.36-10.31) and patients with chronic pancreatitis (8%; OR 7.33, 95% CI 2.54-23.78) but was not significantly different from alcoholic controls (23%; OR 2.27, 95% CI 0.95-5.66). Patients with cirrhosis also had a higher frequency (P < 0.05) of ADH2*1/*1 (100%) than blood donors (92%) and those with chronic pancreatitis (93%). The frequencies of genotypes of ALDH2, CYP2E1, GSTM1, GSTT1 and apolipoprotein E were similar in all groups. CONCLUSION: Alcoholic cirrhosis but not alcoholic chronic pancreatitis is associated with ADH3*2/*2 and perhaps with ADH2*1/*1. Both genes encode less active alcohol-metabolizing enzymes that may be associated with cirrhosis because of delayed formation of acetaldehyde (with higher intakes of alcohol), or diversion of alcohol metabolism through pathways other than ADH.     

Polymorphism of Alcohol-Metabolizing Genes Affects Drinking Behavior and Alcoholic Liver Disease in Japanese Men

Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-45011EI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45011EI genes was determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-Ill-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-45011EI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (<20 g of ethanoVday), the nonflushers were divided into a group of moderate drinkers (20 to 80 glday; n = 54) and a group of heavy drinkers (780 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (29/ 42; 69%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45011EI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDHPl and ADH2*1 alleles, but also a high frequency of the P-45011EI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*l allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45011EI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-45011EI c2 allele.     

Effect of ALDH2 and CYP2E1 Gene Polymorphisms on Drinking Behavior and Alcoholic Liver Disease in Japanese Male Workers

Aims: We examined the relationships of ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease in Japanese male workers.
Methods: Two hundred and eighty-seven Japanese men were selected from one metal company to adjust for similar economic and social backgrounds. Drinking behavior was assessed from a self-assessment questionnaire. Genotypes of ALDH2 and CYP2E1 were analyzed with the polymerase chain reaction-single strand conformation polymorphism and with the polymerase chain reaction-restriction fragment length polymorphism, respectively.
Results: The frequency of the ALDH2 genotype was 55% for typical homozygotes, 42% for heterozygotes, and 4% for atypical homozygotes. The frequency of the CYP2E1 genotype was 62% for c1 homozygotes, 35% for heterozygotes, and 3% for c2 homozygotes. The ALDH2 genotype closely influenced drinking habits, but not the CYP2E1 genotype. Among habitual drinkers, ALDH2 typical homozygotes consumed significantly larger amounts of ethanol than ALDH2 heterozygotes, whereas CYP2E1 genotypes did not influence daily alcohol consumption. Sixteen men (5.6%) were diagnosed with alcoholic liver disease. In terms of ALDH2 genotypes, 12 cases (7.6%) were typical homozygotes and 4 (3.4%) were heterozygotes, whereas the incidence of alcoholic liver disease was not different between c1/c1 homozygotes and c1/c2 heterozygotes. When the interactive contribution of the ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease were examined, there were no significant differences in the CYP2E1 genotype among the subjects with the same ALDH2 genotype.
Conclusion: The ALDH2 genotype is strongly associated with individual alcohol drinking behavior and the development of alcoholic liver disease in Japanese male workers, but the CYP2E1 genotype is not.     

Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen

Introduction: Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or stroke complicate its use. We aimed to determine the allele and genotype frequency of VKORC1 1173 C>T, CYP2C9*2 and CYP2C9*3 variant polymorphisms in the Egyptian population and to evaluate their influence on the interindividual differences in warfarin dosage. Methods: A total of 154 unrelated healthy adult patients and 46 warfarin-treated patients were included. SYBR Green-based real-time polymerase chain reaction (PCR) assay was used for studying VKORC1 (C1173T) and CYP2C9*3 polymorphisms. Mutagenically separated PCR assay was used to detect the CYP2C9*2 allele. Results: VKORC1 genotype frequencies were 11%, 24% and 65% for CC, CT and TT, respectively. The prevalence of CYP2C9 haplotypes was 81% (*1\*1), 3.3% (*1\*2), 9.7% (*1\*3), 4.5% (*2\*2) and 0.65% (2\*3 and *3\*3). VKORC1 TT and CYP2C9*2\*2 were associated with a significantly lower warfarin dose. VKORC1 and CYP2C9 accounted for 31.7% and 15.6% of warfarin dose variability, respectively, and together with clinical factors explained 61.3% of total variability. Conclusion: VKORC1-TT and CYP2C9 *1/*1 are the most prevalent genotypes among Egyptians. Patients with VKORC1-TT genotype required a lower warfarin dose.     

Polymorphisms of Alcohol Dehydrogenase‐1B and Aldehyde Dehydrogenase‐2 and the Blood and Salivary Ethanol and Acetaldehyde Concentrations of Japanese Alcoholic Men

Background: The effects of genetic polymorphism of aldehyde dehydrogenase‐2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase‐1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers. Methods: We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before. Results: The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes. Conclusions: The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer.     

CYP2E1 and ALDH2 Genotypes and Alcohol Dependence in Japanese

The genotypes of the CYP2E1 and ALDH2 loci of alcoholic (alcohol dependence) and nonalcoholic (healthy) Japanese were investigated to examine the relationship between the polymorphism of CYP2E1 (C₁/C₂) and ALDH2 ( ALDH2*1/ALDH2*2 ), and the susceptibility to alcoholism. There was no significant difference in C₂ gene frequency between alcoholics (0.19) and nonalcoholics (controls) (0.20), whereas there was a significant difference in ALDH2 allele frequency, suggesting that, in Japanese, the C₂ genotype of CYP2E1 may have nothing to do with the risk of developing alcohol dependence. However, the ALDH2*1 allele may influence drinking behavior and the development of alcohol dependence. Furthermore, racial interethnic differences in the frequency of the mutated allele of the CYP2E1 gene (CJ were found, like the ALDH2 gene. Japanese healthy controls showed a significantly higher frequency of the C₂ allele than did Swedish healthy controls (0.05; reported by Persson et al., FEBS Lett. 319:207-211,1993).     

Effects of alcohol intake and low Km aldehyde dehydrogenase on hepatic function in a high hepatitis C virus-prevalent Japanese island population

In Asians from the Pacific rim countries, alcohol sensitivity has been attributed mainly to a highly prevalent polymorphism in low Km aldehyde dehydrogenase (ALDH2). Chronic alcohol abuse may accelerate or aggravate the liver injury in chronic hepatitis C virus (HCV)-infected subjects. In this study, we examined the relationships among alcohol intake, ALDH2 genotypes, and liver injury in a high HCV-prevalent Japanese native island population. The ALDH2 genotypes are significantly associated with drinking habits. In HCV RNA positive subjects, serum alanine aminotransferase (ALT), as well as aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT), were significantly higher in habitual drinkers than in nonhabitual drinkers. In male habitual drinkers, the ALDH2*1/*1 subjects had higher liver necroinflammatory scores than the ALDH2*1/*2 subjects in all groups classified as: I, anti-HCV-seronegative; II, anti-HCV-seropositive with negative HCV RNA; and III, HCV RNA positive, although scores for the latter two groups were not statistically significant because of limited sample size. It was suggested that the liver function might be affected by the interaction between the ALDH2 genotypes and alcohol intake. These findings indicate that HCV-infected ALDH2*1/*1 habitual drinkers are the major target for the prevention of alcoholic liver diseases.     

Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele

BACKGROUND: Alcohol metabolism is one of the biological determinants that can influence drinking behavior. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes involved in ethanol metabolism. Allelic variation of the ADH and ALDH genes can significantly affect vulnerability for the development of alcoholism. Homozygosity of the variant ALDH2*2 allele previously was believed to fully protect East Asian populations against the development of alcoholism. METHODS: Eighty Han Chinese alcoholics who met DSM-III-R criteria for alcohol dependence and 144 nonalcohol-dependent subjects were recruited and their data combined with data from 340 alcohol-dependent and 545 nonalcohol-dependent subjects described in an earlier report (Chen et al., 1999) to assess risk for alcoholism by logistic regression analysis. Genotypes of ADH2, ADH3, and ALDH2 were determined by polymerase chain reaction and restriction fragment length polymorphism. The ALDH2 genotype was confirmed by direct nucleotide sequencing. Blood ethanol concentration was determined by headspace gas chromatography and acetaldehyde concentration by high-performance liquid chromatography with fluorescence detection of the derivatized product. Cardiovascular hemodynamic parameters were measured by two-dimensional Doppler echocardiography and sphygmomanometry. Extracranial arterial blood flow was measured by Doppler ultrasonography. RESULTS: An alcohol-dependent patient was identified to be ALDH2*2/*2, ADH2*2/*2, and ADH3*1/*2. Following challenge with a moderate oral dose of ethanol (0.5 g/kg of body weight), the patient exhibited peak concentrations for ethanol (55.7 mg/dl) and acetaldehyde (125 microM). During 130 min postingestion, the patient generally displayed similar or even less intense cardiovascular hemodynamic alterations when compared to a previously published study of nonalcoholic individuals with ALDH2*2/*2 who had received a lower dose of ethanol (0.2 g/kg). Logistic regression analysis of the combinatorial genotypes of ADH2 and ALDH2 in 420 alcohol-dependent and 689 nonalcohol-dependent subjects indicated that risk for alcoholism was 100-fold lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals. CONCLUSIONS: The gene status of ALDH2*2/*2 alone can tremendously but not completely (as thought previously) protect against development of alcohol dependence. Individuals carrying the combinatorial genotype of ADH2*2/*2-ALDH2*2/*2 are at the least risk for the disease in East Asians. Physiological tolerance or innate insensitivity to the accumulation of blood acetaldehyde following alcohol ingestion may be crucial for the development of alcoholism in individuals homozygous for ALDH2*2.     

Mean corpuscular volume and the aldehyde dehydrogenase-2 genotype in male Japanese workers

BACKGROUND: Increased mean corpuscular volume (MCV) is common in alcohol abusers and alcoholics. MCV is higher in Japanese heavy drinkers with inactive aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/2*2 than among those with active ALDH2 encoded by ALDH2*1/2*1. Inactive ALDH2 dramatically increases blood acetaldehyde levels after alcohol intake. Because moderate and heavy drinkers with ALDH2*1/2*2 have very high risks for esophageal cancer, MCV might serve as an indicator of these high-risk drinkers. METHODS: In this investigation of the association of red cell values with the ALDH2 genotype and possible confounding factors, the drinking, smoking, and dietary habits reported on a structured questionnaire by 163 Japanese working men were subjected to multivariate analyses. RESULTS: Aging, lower body mass index (BMI), more alcohol consumption, and more smoking were positively associated with increased MCV. Among moderate to heavy drinkers (>or=9 units/week; 1 unit = 22 g of ethanol), both MCV and mean corpuscular hemoglobin were higher and the red cell count was lower in those with ADLH2*1/2*2 than in those with ALDH2*1/2*1. Multiple linear regression analysis after adjustment for age, BMI, and smoking revealed that a positive relationship between the amount of drinking and MCV but inverse relationships for drinking and red cell count, as well as hemoglobin and hematocrit values, were significantly stronger for men with ALDH2*1/2*2 than for those with ALDH2*1/2*1, demonstrating a gene-environment interaction. Drinking accounted for 19.9% of interindividual MCV variance among men with ALDH2*1/*2*2 but for only 1.3% of variance among those with ALDH2*1/2*1. Age, BMI, drinking, and smoking accounted for 52.1 and 34.7% of the variation among those with ALDH2*1/2*2 and ALDH2*1/2*1, respectively. Macrocytosis (MCV >or=100.0 fl) was observed in 18 subjects (11.0%), and use of macrocytosis as a biomarker of moderate to heavy drinkers with ALDH2*1/2*2 had a sensitivity of 54.5% (6 of 11) and a specificity of 92.1% (140 of 152). CONCLUSIONS: Alcohol-related red cell value changes associated with inactive ALDH2 in Japanese men suggest the importance of acetaldehyde's role in increasing MCV and the potential for using MCV as a marker for high-risk drinkers for esophageal cancer.     

Genetic polymorphisms of alcohol-metabolizing enzymes and cytokines in patients with alcohol induced pancreatitis and alcoholic liver cirrhosis]

BACKGROUND/AIMS: Susceptibility to organ damage induced by alcohol may be related to inherited variations (polymorphisms) in alcohol-metabolizing enzymes, or polymorphisms affecting cytokines. The aim of this study was to compare the genotype and allelic frequencies of ADH2, ADH3, ALDH2, cytochrome P450-2E1, IL-1, IL-6, IL-8 and tumor necrosis factor-alpha in patients with alcoholic pancreatitis and alcoholic liver cirrhosis with those of controls. METHODS: We determined the polymorphism of genes of the above-mentioned alcohol-metabolizing enzymes and cytokines in 29 alcoholic pancreatitis patients (AP), 22 alcoholic liver cirrhosis patients (LC) and 100 healthy blood donors (control). The genotypes were characterized by restriction fragment length polymorphism after amplification of genomic DNA by polymerase chain reaction. RESULTS: The allelic frequency of CYP2E1*c2 was significantly different in three groups (AP: LC: Control=0.224: 0.136: 0.320, p<0.05). There was no significant difference in the other genotypes or allelic frequencies of the three groups. The allelic frequencies of CYP2E1*c2 and ALDH2*2 were more frequent in the control than patients with alcoholic liver cirrhosis (LC: Control=0.136: 0.320, p<0.05, LC: Control= 0.114: 0.265, p<0.05). Allelic frequencies of ADH2 was statistically different between LC and control (ADH2*1; LC: Control=0.727: 0.495, ADH2*2; 0.227: 0.360, ADH2*3; 0.046: 0.145, p<0.05). CONCLUSIONS: There was no difference in the frequencies of genotype and allele of enzymes and cytokines among the three groups. However, frequency of ADH2*1 was significantly higher and those of CYP2E1*c2 and ALDH2*2 were significantly lower than LC group than control.