Analysis of CYP2E1 polymorphism for the determination of genetic susceptibility to gastric cancer in Koreans

BACKGROUND: Interindividual genetic differences in susceptibility to chemical carcinogens are among the most important host factors in human cancer. The present study was undertaken to reveal the association between the polymorphism of CYP2E1 (CYP2E1/PstI and CYP2E1/DraI) with genetic susceptibility to gastric cancer development in Koreans. METHODS: In the present study, 120 gastric cancer patients and 145 controls with no history of tumors were analyzed. CYP2E1 was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP), or PCR and direct gel electrophoresis. RESULTS: The overall genotype distribution of CYP2E1 was not significantly different from that of controls. However, the genotype distribution of the patient subgroups with a history of heavy cigarette smoking (>30 pack/year) in the CYP2E1/PstI and CYP2E1/DraI polymorphisms were significantly different from those of non-smoking patients (P = 0.0122 and P = 0.0029, respectively). The difference was also noticeable in the younger patient subgroup (aged 相似文献   

Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh＇s esophageal squamous cell cancer in Xinjiang, China

AIM: To analyze the relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh's esophageal squamous cell cancer in China. METHODS: The genotypes of cytochromes P450 (CYP) 2E1 and glutathione S-transferase (GST) M1 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) following PCR in 104 Kazakh's patients with esophageal cancer (EC) and 104 non-cancer controls. RESULTS: The frequency of CYP2E1 c1/c1 genotype was significantly higher in patients with cancer (77.9%) than in control subjects (24.0%) (P<0.05; OR, 11.13; 95%CI, 5.84-21.22). The difference of GSTM1 null was significantly more frequent in the cancer (34.6%) vs the control group (3.8%) (P<0.05; OR, 13.24; 95%CI, 4.50-38.89). On the other hand, the combination of GSTM1 presence and CYP2E1 c1/c1 genotypes increased the risk for cancer (P<0.05; OR, 13.42; 95%CI, 6.29-28.3). CONCLUSION: The CYP2E1 c1/c1, GSTM1 deletion genotypes are genetically susceptible biomarkers for ESCC in Kazakh population. Individuals with allele c1 of RsaI polymorphic locus for CYP2E1 may increase the risk of ESCC. Moreover, CYP2E1 wild type (c1/c1) increased the susceptibility to ESCC risk in Kazakh individuals with GSTM1 presence genotype.     

Cytochrome p450 2E1 polymorphisms and the risk of gastric cardia cancer

AIM: Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. Cytochrome P450 2E1 (CYP2E1) enzyme catalyzes the metabolism of many procarcinogens, such as N-nitrosamines and related compounds. The gene coding for this enzyme is polymorphic and thus may play a role in gastric cardia cancer (GCC) etiology. In this hospital-based case-control study, we evaluate the relationship between genetic polymorphisms of CYP2E1 and the risk of GCC. METHODS: The study subjects comprised 159 histologically confirmed GCC cases identified via hospital cancer registry and surgical records at five hospitals in Fuzhou, Fujian Province, China, between April and November 2001. Controls were 192 patients admitted to the same hospitals for nonmalignant conditions. The genotypes of CYP2E1 were detected by a PCR-based RFLP assay. The odds ratios were estimated by logistic regression analyses and were adjusted for potential confounding factors. RESULTS: The distribution of three genotypes of CYP2E1 in GCC cases and controls was significantly different (X2 = 16.04, P<0.01). The frequency of the CYP2E1 (c1/c1) genotype in GCC cases and controls was 60.4% and 40.1%, respectively. The CYP2E1 (c1/c1) genotype was associated with an increased risk for GCC (the adjusted (OR) was 2.37, 95% confidence interval (CI): 1.52-3.70). Subjects who carried the CYP2E1 (c1/c1) genotype and were habitual smokers were at a significantly higher risk of developing GCC (OR = 4.68,95%CT. 2.19-10.04) compared with those who had the CYP2E1 (c1/c2 or c2/c2) genotype and did not smoke. CONCLUSION: These results suggest that the CYP2E1 genotype may influence individual susceptibility to development of GCC, and that the risk increases significantly in smokers.     

Glutathione S-transferases M1, T1 genotypes and the risk of gastric cancer: a case-control study

AIM: Glutathione S-transferases (GSTs) are involved in the detoxification of many potential carcinogens and appear to play a critical role in the protection from the effects of carcinogens. The contribution of glutathione S-transferases M1 and T1 genotypes to susceptibility to the risk of gastric cancer and their interaction with cigarette smoking are still unclear. The aim of this study was to determine whether there was any relationship between genetic polymorphisms of GSTT1 and GSTT1 and gastric cancer. METHODS: A population based case-control study was carried out in a high-risk area, Changle County, Fujian Province, China. The epidemiological data were collected by a standard questionnaire and blood samples were obtained from 95 incidence gastric cancer cases and 94 healthy controls. A polymerase chain reaction method was used to detect the presence or absence of the GSTT1 and GSTT1 genes in genomic DNA. Logistic regression model was employed in the data analysis. RESULTS: An increase in risk for gastric cancer was found among carriers of GSTT1 null genotype. The adjusted odds ratio (OR) was 2.63 95% Confidence Interval (95% CI) 1.17-5.88, after controlling for age, gender, cigarette smoking, alcohol drinking, and fish sauce intake. The frequency of GSTT1 null genotype in cancer cases (43.16%) was not significantly different from that in controls (50.00%). However, the risk for gastric cancer in those with GSTT1 null and GSTT1 non-null genotype was significantly higher than in those with both GSTT1 and GSTT1 non-null genotype (OR = 2.77, 95% CI 1.15-6.77). Compared with those subjects who never smoked and had normal GSTT1 genotype, ORs were 1.60 (95% CI:0.62-4.19) for never smokers with GSTT1 null type, 2.33 (95% CI 0.88-6.28) for smokers with normal GSTT1, and 8.06 (95% CI 2.83-23.67) for smokers with GSTT1 null type. CONCLUSIONS: GSTT1 gene polymorphisms may be associated with genetic susceptibility of stomach cancer and may modulate tobacco-related carcinogenesis of gastric cancer.     

细胞色素P45O 2E1基因多态性与抗结核药物致肝损伤的关系

目的 探讨细胞色素P450(CYP)2E1基因多态性与抗结核药物所致肝损伤(ADIH)的关系.方法 采用病例对照研究设计,选择符合条件的339例结核患者为研究对象,调查其一般情况及肝功能,聚合酶链反应-限制性片段长度多态性分析进行基因分型.数据行单因素和多因素Logistic回归分析.结果 ADIH病例组103例结核患者CYP 2E1的7632T/A、101 9C/T、1259G/C等位基因频率分别为17.5%、26.2%和27.2%,对照组236例结核患者分别为29.7%、39.4%和40.7%(x2=5.539,P＜0.05;x2=5.458,P＜0.05;x2=5.628,P＜0.05).经多因素Logistic回归分析调整了性别、职业、饮酒等危险因素后,7632T/A、1019C/T、1259G/C位点多态性与ADIH的发生仍有相关性,且7632T/A与1019C/T及1259G/C位点野生基因型在ADIH发生过程中起协同作用.结论 携带CYP 2 E1的7632T/A、1019C/T和1259G/C位点野生基因型的个体发生ADIH的危险性增高,且在ADIH的发病过程中起协同作用.     

GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population

MIM:To test the hypothesis that,in the Southeastern Brazilian population,the GSTT1,GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer.METHODS:We conducted a study on 100 cases of gastric cancer(GC),100 cases of chronic gastritis(CG),and 150 controls(C).Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR.CYP2E1/PsА genotyping was performed using a PCR-RFLP assay.RESULTS:No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups.However,a significant difference between CG and C was observde,due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group.The GSTT1 null genotype occurred more frequently in Negroid subjicts,and the GSTM1 null genotype was observed mainly in individuals with chronic gastritis infected with H pylori.CONCLUSION:Our findings indecate that there is no obvious relationship between the GSTT1,GSTM1 and CYP2E1 polymorphisms and gastric cancer.     

CYP2E1和NAT2基因多态性与抗结核药物诱导的药物性肝损伤关系的荟萃分析

目的明确细胞色素氧化酶P450 2E1(cytochrome P450 2E1,CYP2E1)和N-乙酰基转移酶-2(N-acetyltransferase-2,NAT2)基因多态性与抗结核药诱导的药物性肝损伤(anti-tuberculosis drug-induced hepatotoxicity,ATDH)之间的关系。方法计算机检索Medline/Pubmed、EMBASE、Web of Science数据库和Cochrane图书馆中所有有关CYP2E1基因多态性与ATDH关系的研究文献。根据文献纳入及排除标准筛选文献,并对文献进行质量评价。采用OR及95%CI作为分析疗效的统计量。采用Revman 5.0软件统计分析。结果共计纳入研究文献9篇,入选2049例研究对象。CYP2E1基因Pst I/Rsa I多态性中,c1/c1型比c1/c2和c2/c2型有更高的ATDH发生率(OR=1.38,95%CI:1.08~1.77,P=0.01);在Dra I多态性中各型之间无差异(OR=0.78,95%CI:0.51~1.18,P=0.23)。与携带NAT2快速或中速乙酰化的c1/c1型人群比较,携带NAT2慢速乙酰化的c1/c1型人群具有更高的ATDH风险(OR=3.10,P0.0001)。结论 CYP2E1基因c1/c1型是ATDH发生的风险因素,且合并慢速乙酰化的NAT2基因型时可进一步增加ATDH发生率。     

CYP2E1 Rsa Ⅰ polymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

AIM： To investigate associations between the Rsa I polymorphism of CYP2E1 and risk of colorectal cancer. METHODS： A case-control study was conducted with 315 colorectal cancer cases （105 colon, 210 rectal） and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1 by PCR amplification followed by digestion with Rsa I. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios （ORs） were estimated with an unconditional logistic model. RESULTS： The proportional distribution of the CYP2E1 Rsa I c1/c1, c1/c2 and c2/c2 genotypes were 61.4%, 35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8% in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant differencewas noted between controls and rectal cancer cases （P = 0.029）, the c2/c2 genotype being associated with elevated OR （adjusted age, sex and status of the smoking and alcohol drinking） for rectal cancer （1.64, 95% CI, 1.12-2.41, vs cl allele carriers）, but not for colon cancer. In interaction analysis between the CYP2E1 Rsa I genotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon （4.74, 95% CI, 1.10-20.40） and rectal （5.75, 95% CI, 1.65-20.05） cancers. Among nonsmokers, the CYP2E1 Rsa I c2/c2 genotype was also associated with elevated ORs in the two sites （1.95, 95% CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99）. CONCLUSION： The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.     

CYP2E1 Rsa Ⅰ polymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

AIM: To investigate associations between the Rsa Ⅰpolymorphism of CYP2E1 and risk of colorectal cancer.METHODS: A case-control study was conducted with 315 colorectal cancer cases (105 colon, 210 rectal)and 439 population-based controls in Jiangsu Province of China. Genomic DNA samples were assayed for restriction fragment length polymorphisms in CYP2E1by PCR amplification followed by digestion with Rsa Ⅰ. Information on smoking and alcohol drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model.RESULTS: The proportional distribution of the CYP2E1 Rsa Ⅰ c1/c1, c1/c2 and c2/c2 genotypes were 61.4%,35.6% and 3.0% in controls, 60.6%, 33.7% and 5.8%in colon cancer cases, and 58.4%, 34.0% and 7.7% in rectal cancer cases, respectively. A significant difference was noted between controls and rectal cancer cases (P = 0.029), the c2/c2 genotype being associated with elevated OR (adjusted age, sex and status of the smoking and alcohol drinking) for rectal cancer (1.64,95% CI, 1.12-2.41, vs c1 allele carriers), but not for colon cancer. In interaction analysis between the CYP2E1Rsa Ⅰ genotype and smoking and drinking habits, we found a significant cooperative action between the c2/c2 genotype and alcohol drinking in the sex-, age-adjusted ORs for both colon (4.74, 95% CI, 1.10-20.40) and rectal (5.75, 95% CI, 1.65-20.05) cancers. Among nonsmokers, the CYP2E1 Rsa Ⅰ c2/c2 genotype was also associated with elevated ORs in the two sites (1.95, 95%CI, 0.99-3.86 and 2.30, 95% CI, 1.32-3.99).CONCLUSION: The results of the present study suggest that the CYP2E1 c2/c2 genotype increases susceptibility to rectal cancer and the gene-environmental interactions between the CYP2E1 polymorphism and smoking or alcohol drinking exist for colorectal neoplasia in general.     

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.     

CYP2C19 polymorphisms in patients with gastric and colorectal carcinoma

Background It has been reported that up to 80% of human cancer arise as a consequence of environmental exposure and host susceptibility factors. Environmental carcinogens are predominantly metabolized by the cytochrome P450 (CYP) superfamily of drug-or xenobiotic-metabolizing enzymes. Genetic variations in these enzymes affect individuals' susceptibility to carcinogens. Aim of the study The aim of this study was to evaluate the relationship between CYP2C19 polymorphism and susceptibility to these cancers by means of CYP2C19 genotyping among Turkish subjects. Methods DNA of subjects were isolated from leukocytes by high pure template preparation kit (Roche Diagnostics, GmbH, Mannheim, Germany) and genotypes were detected by LightCycler CYP2C19 Mutation Detection Kit by real-time PCR with LightCycler instrument (Roche Diagnostics, cat. no. 3113914). Results Being male was associated with a 3.5-fold (OR: 4.27, CI: 2.27–8.05) and 4.27-fold (OR: 3.50, CI: 1.948–6.301) risk for colorectal and gastric carcinoma, respectively. The CYP2C19 ^* 3 heterozygote genotype was not found in either gastric or colorectal carcinoma patients. Although the frequency of CYP2C19^*2 heterozygote genotype is high in patients with gastric and colorectal carcinoma, it is not significantly associated with cancer (OR: 1.79, CI: 0.829–3.865 and OR: 1.998, CI: 0.961–4.154, respectively). Conclusion Although the frequency of CYP2C19 ^* 2 heterozygote genotype is high in our patients with gastric and colorectal carcinoma, there is no the relationship between CYP2C19 polymorphism and susceptibility to these cancer.     

基因多态性及常见危险因素与胃癌易患性的研究

目的探讨中国汉族人群细胞色素P450(CYP)1A1基因型、谷胱甘肽巯基转移酶(GST) M1基因型及常见危险因素与胃癌易患性的关系,为胃癌高危人群的确定和胃癌的一级预防提供分子生物学手段。方法所有研究对象经胃镜和病理检查分为胃癌(GC,仅包括胃腺癌)组102例、慢性萎缩性胃炎(CAG)组110例、慢性浅表性胃炎(CSG)组110例、胃溃疡(GU)组62例、十二指肠溃疡(DU)组62例及正常对照组62例。采用统一的调查表对每个研究对象进行调查,调查项目包括年龄、性别、学历、职业、吸炯史、饮酒史、饮食习惯、肿瘤家族史等。采用序列特异性引物的聚合酶链反应(PCR-SSP)方法检测CYP1A1基因型及GSTM1基因型测定组的基因型频率,ELISA法测定幽门螺杆菌(Hp)感染,病例对照研究方法进行流行病学分析。结果单因素分析显示与胃癌有关联的危险因素为年龄、性别、文化程度、职业、Hp感染、吸烟、CYP1A1 G/G基因型、GSTM1空白基因型,其中大蒜为保护性因素;多因素分析显示与胃癌有关联的危险因素分别为Hp感染、CYP1A1 G/G基因型、GSTM1空白基因型,大蒜仍为保护性因素。CYP1A1 G／G基因型及GSTM1空白基因型对胃癌的发生具有协同作用。Hp感染与CYP1A1 G／G基因型、GSTM1空白基因型对胃癌的发生存在协同作用;吸烟与CYP1A1 G/G基因型、GSTM1空白基因型存在协同作用。结论具有CYP1A1 G/G或GSTM1基因型的个体发生胃癌的危险性增加,而同时有两种基因型的个体发生胃癌的危险性更高,这两种基因型可以认为是胃癌易患性的标志。     

CYP2E1 Pst Ⅰ/Rsa Ⅰ polymorphism and colorectal cancer risk:A meta-analysis

AIM:To clarify the association between CYP2E1 PstⅠ/RsaⅠ polymorphism and susceptibility to colorectal cancer.METHODS:A meta-analysis based on 10 eligible casecontrol studies involving 4979 cases and 6012 controls was carried out to summarize the data on the association between CYP2E1 RsaⅠ/PstⅠ polymorphism and colorectal cancer risk.RESULTS:In comparison of the homozygote c2c2 and c2 carriers(c1c2 + c2c2) and the homozygous wild-type genotype(c1c1),no association was found between CYP2E1 RsaⅠ/PstⅠ polymorph...     

Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males

AIM：To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma （ESCC） in a high risk area of Gansu Province, in Chinese males.
METHODS： A case-control study was conducted to investigate the genetic polymorphisms of these enzymes （CYP2E1 ＊c1/＊c2, ALDH2 ＊1/＊2 and ADH1B ＊1/＊1 genotypes）. A total of 80 esophageal cancer cases and 480 controls were recruited.
RESULTS： Compared with controls, cases had a greater prevalence of heavier alcohol consumption （53.8% vs 16.2%） and a higher proportion of alcohol drinkers with 〉 30 drink-years （28.8% vs 13.5%）. Heavier alcohol consumption and alcohol drinking with 〉 30 drink- years increased the risk of ESCC, with ORs （95% CI） of 3.20 （1.32-9.65） and 1.68 （0.96-3.21）. CYP2E1 （＊c1/＊c1）, ALDH2 （＊1/＊2） and ADH1B （＊1/＊1） genotype frequencies were higher among patients with squamous cell carcinomas, at a level close to statistical significance （P = 0.014; P = 0.094; P = 0.0001 respectively）. There were synergistic interactions among alcohol drinking and ALDH2, ADH1B and CYP2E1 genotypes. The risk of the ESCC in moderate-to-heavy drinkers with an inactive ALDH2 encoded by ALDH2 ＊1/＊2 as well as ADH1B encoded by ADH1B ＊1/＊1 and CYP2E1 encoded by CYP2E1 ＊c1/＊c1 was higher than that in the never/rare-to-light drinkers with an active ALDH2 （＊1/＊1 genotype） as well as ADH1B （＊1/＊2 ＋ ＊2/＊2） and CYP2E1 （＊c1/＊c2 ＋ ＊c2/＊c2） genotypes, with a statistically significant difference; ORs （95% CI） of 8.58 （3.28-22.68）, 27.12 （8.52-70.19） and 7.64 （2.82-11.31） respectively. The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 （＊1/＊2） combined the ADH1B （＊1/＊1） genotype or ALDH2 （＊1/＊2） combined the CYP2E1 （＊c1/＊c1） genotype leads to synergistic interactions, higher than drinkers with ALDH2 （＊1/＊1） ＋ ADH1B （＊1/＊2 ＋ ＊2/＊     

Interaction of methylenetetrahydrofolate reductase C677T,cytochrome P4502E1 polymorphism and environment factors in esophageal cancer in Kazakh population

AIM： To evaluate the association and interaction of genetic polymorphisms in methylenetetrahydrofolate reductase （MTHER） and cytochrome P4502E1 （CY- P4502E1）, environment risk factors with esophageal cancer （EC） in Kazakh, a high EC incidence area of Xinjiang Uygur Autonomous Region, China. METHODS： A 1：2 matched case-control study was conducted with 120 cases of EC and 240 populationor hospital-based controls. The controls were matched for sex, nationality, area of residence and age within a 5-year difference. MTHER and CYP4502E1 genotypes were identified by PCR-based restriction fragment length polymorphism （RFLP）. A conditional logistic regression model was established to identify risk factors. The strata method was adopted in interaction analysis. RESULTS： Low consumption of green vegetables and fresh fruits, alcohol drinking, and unsafe water （shallow well, or river） were found to be the risk factors for EC. Individuals with the MTHFR677 （C/T ＋ T/T） genotype had a 2.62-fold （95% CI： 1.61-4.28） risk of developing EC compared with those who carried the C/C genotype. Individuals with the CYP4502EIC1/C1 genotype had a 3.00-fold （95% CI： 1.82-4.96） risk compared with those who carried the CYP4502E1 （C1/C2 ＋ C2/C2） genotype. Gene-environment interaction analysis showed that MTHFR677 gene polymorphism was correlated with consumption of green vegetables and fresh fruit, while CYP4502E1 C1/C1 was correlated with alcohol drinking and unsafe drinking water. MTHFR and CYP4502E1 analysis of gene-gene interaction showed that individuals with the MTHFR677 （C/T ＋ T/T） and CYP4502EIC1/ C1 genotypes had a 7.41-fold （95% CI： 3.60-15.25） risk of developing EC compared with those who carried the MTHFR677C/C and CYP4502E1 RsaI C1/C2 ＋ C2/C2 genes, and the interaction rate was higher than that of the two factors alone. CONCLUSION： Low consumption of green vegetables and fresh fruits, alcohol drinking, and unsafe water （shallow well, or river） and polymorphisms     

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.     

Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis

Background and Aim: Antituberculosis drugs, isoniazid and rifampicin, in combination, are known to develop drug‐induced hepatotoxicity (DIH). A higher risk of DIH during antituberculosis treatment (ATT) has been reported in the Indian subcontinent compared to its Western counterparts. The role of genetic factors in a higher incidence of ATT hepatotoxicity in the Indian population is still unclear. The present study was aimed at investigating the role of the N‐acetyltransferase2 (NAT2) and cytochrome P4502E1 (CYP2E1) gene polymorphisms in ATT hepatotoxicity. Methods: The study population included 218 pulmonary tuberculosis patients who were started on ATT and followed up for the occurrence of ATT‐induced hepatitis. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by polymerase chain reaction–restriction fragment length polymorphism. Results: The occurrence of DIH was 18.8% (41/218). There was a higher prevalence of NAT2 slow‐acetylator genotypes in DIH (70.73%) compared to non‐DIH (44.63%; P < 0.05). The frequency of the NAT2*5/*7 and NAT2*6/*7 genotypes was significantly higher in DIH than non‐DIH (19.51% vs 6.78%, and 19.51% vs 5.08%). No association of the CYP2E1 RsaI polymorphism could be demonstrated with DIH. However, the DraI C/D genotype of the CYP2E1 gene was mostly prevalent in DIH (85.37%), compared to non‐DIH (64.41%) (P < 0.05). Slow‐acetylator status and the CYP2E1 C/D or C/C genotype together showed a higher frequency in DIH (65.85%) compared to non‐DIH (28.81%) (P < 0.0001). Conclusion: The study demonstrates for the first time a possible association between the DraI polymorphism of the CYP2E1 gene and the risk of ATT hepatotoxicity. The genotyping of the NAT2 and CYP2E1 genes could possibly identify the groups at highest risk of developing ATT‐induced hepatitis prior to medication.     

CYP1A1, CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms

AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.     

Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer

Background Genetic polymorphisms of drug-metabolizing enzymes have recently been shown to affect susceptibility to chemical carcinogenesis. However, the molecular mechanisms of individual susceptibility to gastric cancer have not been fully understood. Therefore, we studied the relationship between the genetic polymorphisms of drug-metabolizing enzymes, drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer.Methods The genotypes of cytochromes P450 (CYP) 1A1 and 2E1, glutathione S-transferase (GST) M1, and N-acetyltransferase (NAT) were investigated by polymerase chain reaction (PCR), allele-specific PCR, or restriction fragment length polymorphism (RFLP) following PCR in 146 Japanese patients with gastric cancer (67 intestinal-type and 79 diffuse-type carcinomas) and 177 autopsied controls. In addition, p53 gene point mutations of exons 5 through 9 in gastric cancer tissues were determined.Results The frequency of either being a habitual drinker or having a CYP2E1^*1A/^*1A genotype was significantly higher in patients with intestinal-type gastric cancer than in control subjects. The difference between the frequencies of habitual drinkers with the CYP2E1^*1A/^*1A genotype and non-drinkers with the CYP2E1^*5B allele was much more significant in the intestinal-type cancer versus the control group. Among intestinal-type cancer patients with the CYP2E1^*1A/^*1A genotype, p53 point mutations were significantly more frequent in the group of habitual drinkers than in that of non-drinkers. On the other hand, the combination of GSTM1 null and CYP2E1^*1A/^*1A genotypes increased the risk for diffuse-type gastric cancer, but had no influence on the frequency of p53 gene mutations.Conclusions The present study suggests that individuals with both the CYP2E1^*1A/^*1A genotype and a history of habitual drinking have an increased risk of intestinal-type gastric cancer with a high frequency of p53 gene point mutations in the gastric mucosa.