Contribution of the alcohol dehydrogenase-1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men

The less-active homozygous alcohol dehydrogenase-1B (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level (相似文献   

Development of squamous neoplasia in esophageal iodine-unstained lesions and the alcohol and aldehyde dehydrogenase genotypes of Japanese alcoholic men

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥ 5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes.     

p53 protein accumulation, iodine-unstained lesions, and alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes in Japanese alcoholic men with esophageal dysplasia

Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2(*)1/(*)2) and less-active alcohol dehydrogenase-1B (ADH1B(*)1/(*)1) increase the risk of esophageal cancer in East Asian drinkers, and esophageal cancer multiplicity is strongly associated with ALDH2(*)1/(*)2. p53 alterations are key molecular events in multifocal carcinogenesis in the esophagus. We studied 260 esophageal-cancer free Japanese alcoholics with esophageal dysplasia diagnosed by biopsy of distinct iodine-unstained lesions (DIULs) ≥5mm. The degree of p53 protein accumulation was positively associated with the degree of atypia (p<0.0001) and size (p=0.040) of DIULs and with the presence of multiple DIULs (p=0.070), but not with ALDH2(*)1/(*)2 or ADH1B(*)1/(*)1.     

Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females

Aim: Alcohol dehydrogenase-IB (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are the key enzymes for elimination of ethanol and acetaldehyde, the latter being an established animal carcinogen produced after drinking. In this study, we aimed to evaluate the contribution of ADH1B and ALDH2 polymorphisms to the risk of esophageal squamous cell (ESCC) in Chinese females. Methods: A total of 81 pathologically-proven female ESCC cases and 162 female controls were recruited from the Affiliated Hospital of Medical College of Armed Police Forces of PRC in China. ADH1B and ALDH2 polymorphisms were genotyped using PCR-CTPP. Results: Compared with those with ADH1B*2/*2, individuals with ADH2*1/*2 and ADH2*1/*1 had 1.47 and 2.36-fold, respectively, increased risk of developing ESCC (95%CI=0.84-2.58, 95%CI=1.14-5.79) after adjusting for alcohol consumption and other covariates. Significantly increased risk was also noted among subjects with ALDH2*1/*2 (adjusted OR=3.24, 95%CI=1.45-5.36), when compared to those with ALDH2*1/*1. Risk was greater in heavy drinking females carrying ADH1B *1/*1 or ALDH2*1/*2 genotypes compared to those with ADH1B*2 and ALDH2*1/*1. Moreover, we found a significant trend of ESCC risk with alcoholic consumption in women with ALDH2*1/*2. Conclusion: Chinese women with ADH1B *1/*1 or ALDH2*1/*2 have elevated risk of ESCC similarly to men. Women with inactive ADH1B and ALDH2 should reduce drinking and increase their intake of vegetable and fruit to prevent development of esophageal cancer.     

Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer-free alcoholic Japanese men: an endoscopic follow-up study.

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.     

Macrocytosis,a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men

Early esophageal squamous cell carcinoma detected by esophageal iodine staining can be easily treated by endoscopic mucosectomy, and identifying its predictors is important in better selecting candidates to screen for this high-mortality cancer. The common etiologies of elevated mean corpuscular volume (MCV) and esophageal cancer, including folate deficiency, smoking, drinking and high acetaldehyde exposure, suggest testing MCV as such a predictor. Japanese alcoholic men with (n = 65) and without (n = 206) esophageal squamous cell carcinomas, excluding those with liver cirrhosis, were assessed for MCV within 7 days of their last drink, alone or in combination with findings from either the alcohol flushing questionnaire or genotyping to identify inactive aldehyde dehydrogenase-2 (ALDH2*1/2*2) and the less-active form of alcohol dehydrogenase-2 (ADH2*1/2*1), which pose risks for esophageal squamous cell carcinoma. MCV was higher in cancer patients than in the control group. MCV was higher in both groups in those who were heavier smokers, had lower body mass index (BMI), experienced alcohol flushing, and had ALDH2*1/2*2. After adjusting for age, drinking and smoking habits, BMI and ALDH2/ADH2 genotypes, macrocytosis of MCV > or =106 fl was associated with increased risk for esophageal cancer (OR = 2.75). Men with both MCV > or =106 fl and alcohol flushing had an even higher cancer risk (OR = 5.51). The combinations of MCV > or =106 fl with ALDH2*1/2*2 or ADH2*1/2*1 alone, and both ALDH2*1/2*2 and ADH2*1/2*1 (ORs = 11.44, 21.22 and 319.7, respectively) showed consistently higher risk than the corresponding group with MCV <106 fl (ORs = 7.24, 4.71 and 27.01, respectively). In conclusion, MCV measurement, alone or in combination with the markers of alcohol sensitivity, provides a new means of predicting risk for esophageal squamous cell carcinoma in Japanese alcoholic men.     

Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case-control study was conducted. Here, 406 patients with pathology-proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low-to-moderate (0.1-30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low-to-moderate drinkers, a smoking-dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk.     

Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a chinese population.

Objective: To investigate the relationship of alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genotypes as well as alcohol drinking to the susceptibility of primary hepatocellular carcinoma (HCC). Methods: A case-control study including 208 cases of HCC and 208 controls matched with sex, age and residential area was carried out in Taixing city of Jiangsu province, China. Blood samples were collected and tested for ADH2 and ALDH2 genotypes by PCR-RFLP method. Results: There were no significant differences in the frequency of either ADH2 or ALDH2 genotypes between cases and controls. Compared with no-drinkers possessing ALDH21*1 genotypes, drinkers with ALDH21*2 or ALDH22*2 genotypes and cumulative amount of alcohol consumption >3 (Kg * years) were at a significantly higher risk of developing HCC (OR=3.30, 95%CI: 1.24-8.83). In contrast, there was no significant difference in cancer risk between no-drinkers with ADH21*1 and drinkers with ADH2 1*2 or ADH22*2 genotypes. A dose-dependent positive result was found (P=0.044) between cumulative amount of alcohol consumption and the risk of HCC in individuals carrying ALDH21*2 or ALDH22*2 genotypes. Drinkers with cumulative amount of alcohol consumption >3 (Kg * years) who possessed both inactive ALDH2 (ALDH21*2 or ALDH22*2) and inactive ADH (ADH21*2 or ADH22*2) genotypes were not at a significantly higher risk of HCC (adjusted OR=4.26, 95%CI: 0.63-29.08) compared to no-drinkers possessing ADH21*1 and ALDH21*1 genotypes. Compared with individuals possessing ALDH21*1, with negative HBsAg and cumulative amount of alcohol consumption 3 (Kg * years) had a significantly higher risk of HCC (OR=49.71, 95%CI: 5.51-448.96). Conclusion: These results revealed that it was not ADH2 but ALDH2 polymorphisms that had a significant interaction with heavy alcohol consumption in the development of HCC. This result suggests that to help lower their risk for HCC , persons with ALDH21*2 or ALDH22*2 genotypes should be encouraged to reduce their consumption of alcoholic beverages.     

Lifestyle habits and genetic susceptibility and the risk of esophageal cancer in the Thai population

The association of lifestyle habits and polymorphism of ADH2 and ALDH2 genes with the risk of esophageal cancer in Thai population was investigated in a hospital-based case-control study: 202 cases and 261 controls. The results of multivariate logistic analysis showed that alcohol consumption >60g/day, smoking >10 cigarettes/day and chewing betel >or=10 quids/day significantly increased risk (odds ratio (OR) 5.84, 95% confidence interval (CI) 3.15-10.83; 4.65, 95% CI 1.99-10.84; and 4.68, 95% CI 2.05-10.72, respectively). ADH2*1/*1 also increased the risk significantly (OR 1.56, 95% CI 1.01-2.39) while ALDH2 did not (OR of ALDH2*1/*2 1.57, 95% CI 0.89-2.76). However, the combined at risk genotypes, ADH2*1/*1 and ALDH2*1/*2 increased risk to four-fold. In addition, significant gene-environment interaction was found. Heavy drinkers >60g/d harboring ADH2*1/*1 or ALDH2*1/*2 had about an 11-fold increased risk.     

Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks

In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer. A multicenter hospital-based case-control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1-4). Polymorphisms of ADH1B and ALDH2 were genotyped by the method of PCR-RFLP. Individuals with ADH1B*1/*1 genotype had a 3.99-fold risk (95% CI = 2.13-7.48) of developing esophageal cancer, compared with those with ADH1B*2/*2 genotype, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99-fold risk (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, of developing esophageal cancer, compared with those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes of ADH1B and ALDH2 on esophageal cancer risk. These results suggest that ADH1B and ALDH2 polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.     

Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers

Alcoholic beverages are causally related to cancer of the oral cavity, pharynx, larynx and esophagus. Ethanol is oxidized to acetaldehyde and then to acetate by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), both of which have genetic polymorphisms. A review of case-control studies of the effects of ALDH2, ADH2 and ADH3 genotypes shows consistently positive associations between inactive heterozygous ALDH2 and the less-active ADH2 genotypes and the risk for esophageal cancer in East Asian heavy drinkers and this enzyme-related vulnerability may extend to light-to-moderate drinkers. Some studies suggest similar associations with the risk for head and neck cancer in moderate-to-heavy-drinking Japanese. An established carcinogen in experimental animals, acetaldehyde can interact with human DNA. ALDH2-associated cancer susceptibility fits into a scenario in which acetaldehyde plays a critical role in the development of human cancer. Alcohol flushing and drinking behavior may partly explain this carcinogenic effect in carriers of less-active ADH2 genotypes. Whether the ADH3 genotype influences head and neck cancer risk in Western nations is controversial. Professional and public education about risky conditions connected to the ALDH2 and ADH2 genotypes and environmental factors is important in a new strategic approach to the prevention of alcohol-related cancers in East Asians. The use of simple tests to identify inactive ALDH2 on the basis of alcohol flushing responses could benefit many people, by helping them to identify their own cancer risks. Such testing could also help clinicians diagnose esophageal cancer earlier, through the use of endoscopic screening in the high-risk population.     

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.     

Alcohol Dehydrogenase-2 and Aldehyde Dehydrogenase-2 Genotypes,Alcohol Drinking and the Risk for Stomach Cancer in Chinese Males

Objective: To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption, and the susceptibility of stomach cancer in Chinese males. Methods: Three hundred and eighty-two stomach cancer patients and 382 healthy controls from Taixing and Changshu city of Jiangsu province were enrolled in this study. ADH2 and ALDH2 genotypes were examined by PCR and denaturing high-performance liquid chromatography (DHPLC). Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence intervals (95% CI). Results: (1) In no drinkers, compared with ALDH2G/G carriers, ALDH2 G/A (OR=1.67, 95%CI: 1.01-2.78) carriers showed a significantly elevated risk of developing stomach cancer. No association was found between ADH2 genotypes and risk of stomach cancer. (2) ALDH2 A allele carriers with cumulative amount of alcohol consumption ≥2.5 (Kg * years) were at a higher risk of developing stomach cancer compared with those with cumulative amount of alcohol consumption <2.5Kg (Kg * years) (OR=2.72, 95%CI:0.89-8.31) and ALDH2 G/G carriers with cumulative amount of alcohol consumption <2.5 (Kg * years) (OR=2.46, 95%CI=0.90-6.72) or ≥2.5 (Kg * years) (OR=2.53, 95%CI=0.86-7.49). (3) Compared with individuals with ADH2 A/A and ALDH2 G/G genotypes, ADH2 G and ALDH2 A allele carriers were not at a high risk of developing stomach cancer, with regard to the status of alcohol consumption, and even cumulative amount of alcohol consumption ≥1.5 (Kg * years) (OR =1.65, 95%CI:0.56-4.82). Conclusion: ADH2 and ALDH2 polymorphisms and alcohol drinking may not play an important role in the development of stomach cancer in Chinese males.     

p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.     

Meta-analysis of ALDH2 variants and esophageal cancer in Asians

Alcohol drinking is considered a risk factor for esophageal cancer, and exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be responsible. Individuals homozygous for the *2 variant allele of aldehyde dehydrogenase 2 (ALDH2) are unable to metabolize acetaldehyde, which prevents them from alcohol drinking, whereas those with *1/*2 have a 6-fold higher blood acetaldehyde concentration postalcohol consumption with respect to *1*1. We carried out a meta-analysis of ALDH2 and esophageal cancer searching for relevant studies on Asians in Medline and EMbase up to May 2011, and investigated the association between this genotype variation and esophageal cancer risk. A total of 2,697 cases and ,6344 controls were retained for the analysis. The pooled OR (95% CI) for ALDH2*1/*2 was 2.47 (95%CI: 1.76-3.46) compared with ALDH2*1/*1. ALDH2*2/*2 showed a non-significant decreased risk for esophageal cancer with OR of 0.6 (0.26-1.38). ALDH2*1/*2 individuals showed a higher risk of esophageal cancer among moderate and heavy alcohol users [2.17(1.95-2.43) and 3.20(2.78-3.70), respectively]. Moderate drinkers with ALDH2*2/*2 showed strong esophageal cancer risk [OR(95%CI)=8.52(3.81-19.04)] compared with ALDH2*1/*1 carriers among heavy drinkers than non-drinkers and moderate drinkers (OR=7.05). Our finding showed that ALDH2*1/*2 genotype increases the risk of esophageal cancer, while the ALDH2*2/*2 genotype reduces the risk, presumably preventing people from consumption due to discomfort. Drinking clearly modifies the effect of ALDH2 on esophageal cancer risk in Asians.     

Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics

Alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) gene polymorphisms play roles in ethanol metabolism, drinking behavior and esophageal carcinogenesis in Japanese; however, the combined influence of ADH2 and ALDH2 genotypes on other aerodigestive tract cancers have not been investigated. ADH2/ALDH2 genotyping was performed on lymphocyte DNA samples from Japanese alcoholic men (526 cancer-free; 159 with solitary or multiple aerodigestive tract cancers, including 33 oropharyngolaryngeal, 112 esophageal, 38 stomach and 22 multiple primary cancers in two or three organs). After adjustment for age, drinking and smoking habits, and ADH2/ALDH2 genotypes, the presence of either ADH2*1/2*1 or ALDH2*1/2*2 significantly increased the risk for oropharyngolaryngeal cancer [odds ratios (ORs), 6.68 with ADH2*1/2*1 and 18.52 with ALDH2*1/2*2] and esophageal cancer (ORs, 2.64 and 13.50, respectively). For patients with both ADH2*1/2*1 and ALDH2*1/2*2, the risks for oropharyngolaryngeal and esophageal cancers were enhanced in a multiplicative fashion (OR = 121.77 and 40.40, respectively). A positive association with ALDH2*1/2*2 alone was observed for stomach cancer patients who also had oropharyngolaryngeal and/or esophageal cancer (OR = 110.58), but it was not observed for those with stomach cancer alone. Furthermore, in the presence of ALDH2*1/2*2, the risks for multiple intra-esophageal cancers (OR = 3.43) and for esophageal cancer with oropharyngolaryngeal and/or stomach cancer (OR = 3.95) were higher than the risks for solitary intra-esophageal cancer and for esophageal cancer alone, but these tendencies were not observed for ADH2*1/2*1 genotype. Alcoholics' population attributable risks due to ADH2/ALDH2 polymorphisms were estimated to be 82.0% for oropharyngolaryngeal cancer and 63.9% for esophageal cancer.     

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.     

饮酒及酒精代谢酶基因多态与食管癌发病风险

[目的]研究饮酒及乙醇脱氢酶2（ADH2）和乙醛脱氢酶2（ALDH2）基因多态性与食管癌发病风险关系。[方法]对江苏省泰兴市221食管癌新发病例和191对照调查饮酒习惯等因素,采用聚合酶链反应（PCR）和变性高效液相色谱法（DHPLC）检测研究对象ADH2和ALDH2基因型。[结果]①携带ALDH2 G/A或A/A饮酒者患食管癌危险性,分别是携带ALDH2G/G饮酒者或不饮酒者的3.08倍和3.05倍（OR=3.08,95%CI：1.65～5.78;OR=3.05,95%CI：1.49～6.25）。②携带ALDH2 G/A或A/A且酒精消耗总量≥2.5kg·年者患食管癌风险是携带ALDH2G/G且酒精消耗总量〈2.5kg·年者12.31倍（OR=12.31,95%CI：3.01～50.37）。③携带ALDH2 G/A或A/A者患食管癌风险,随酒精消耗总量增加呈趋势性显著上升（P=0.023）,当达到≥2.5kg·年时患食管癌风险是不饮酒者的6.58倍。④同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G且酒精消耗总量≥2.5kg·年者患食管癌风险,是同时携带ALDH2G/G和ADH2A/A且酒精消耗总量〈2.5kg·年者（OR=35.59,95%CI：1.86～680.1）。[结论]可将酒精消耗总量达≥2.5kg·年作为显著增加携带ALDH2 G/A或A/A饮酒者患食道癌风险的阈值。对同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G且酒精消耗总量≥2.5kg·年者,劝其戒酒和定期随访对降低食管癌危害十分有益。     

Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking,smoking, and diet in Japanese men with esophageal squamous cell carcinoma

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2),alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferaseM1 (GSTM1) influence the metabolism of alcohol and other carcinogens.The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, andADH2*1/2*1, which encodes the low-activity form of ADH2, enhancethe risk for esophageal cancer in East Asian alcoholics. Thiscase–control study of whether the enzyme-related vulnerabilityfor esophageal cancer can be extended to a general populationinvolved 234 Japanese men with esophageal squamous cell carcinomaand 634 cancer-free Japanese men who received annual healthcheckups. The GSTM1 genotype was not associated with the riskfor this cancer. Light drinkers (1–8.9 units/week) withALDH2*1/2*2 had an esophageal cancer risk 5.82 times that oflight drinkers with ALDH2*1/2*1 (reference category), and theirrisk was similar to that of moderate drinkers (9–17.9units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk formoderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded thatfor heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38).Similar increased risks were observed for those with ADH2*1/2*1.A multiple logistic model including ALDH2, ADH2, and ADH3 genotypesshowed that the ADH3 genotype does not significantly affectthe risk for esophageal cancer. For individuals with both ALDH2*1/2*2and ADH2*1/2*1, the risk of esophageal cancer was enhanced ina multiplicative fashion (OR = 30.12), whereas for those witheither ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and4.11. In comparison with the estimated population-attributablerisks for preference for strong alcoholic beverages (30.7%),smoking (53.6%) and for lower intake of green and yellow vegetables(25.7%) and fruit (37.6%), an extraordinarily high proportionof the excessive risk for esophageal cancer in the Japanesemales can be attributed to drinking (90.9%), particularly drinkingby persons with inactive heterozygous ALDH2 (68.5%). Educationregarding these risky conditions in connection with ALDH2 andADH2 is vitally important in a new strategic approach aimedat preventing esophageal cancer in East Asians.     

醇醛脱氢酶基因多态及饮酒习惯与胃癌易感性

[目的]探讨乙醇脱氢酶2（ADH2）和乙醛脱氢酶2（ALDH2）基因多态及饮酒习惯与胃癌易感性的关系。[方法]选取江苏省泰兴市和常熟市382例男性胃癌新发病例作为病例组,同时按同居住地、同性别及年龄±2岁1：1个体匹配抽取对照。收集所有研究对象的饮酒习惯等因素。采用聚合酶链反应（PCR）和变性高效液相色谱法（DHPLC）检测研究对象ADH2和ALDH2基因型。[结果]①病例组与对照组相比,ADH2和ALDH2各基因型分布频度差异均未达统计学意义。（9携带ALDH2G／A或A／A且酒精消耗总量≥2．5kg·年者,患胃癌的OR值分别是携带ALDH2G／G且酒精消耗总量〈2．5kg·年及≥2．5kg·年者的2．53（95％CI：0．86—7．49）和2．46（95％CI：0．90～6．72）倍,亦是携带ALDH2G／A或A／A且酒精消耗总量〈2．5kg·年者的2．72（95％CI：0．89～8-31）倍,但差异均未达到统计学意义（P〉0．05）。②与同时携带ADH2A／A和AI。DH2G／G者相比．同时携带ADH2G／A或G／G和ALDH2G／A或A,A者无论是否饮酒,患胃癌风险均无明显增加,即使当饮酒者的酒精消耗总量≥2．5kg·年亦如此（OR=3．13,95％CI：0．78,12．64）。[结论]本研究未发现ADH2和ALDH2基因多态及饮酒与胃癌易感性有关。