CYP2E1 T7632A and 9-bp insertion polymorphisms and colorectal cancer risk: a meta-analysis based on 4,592 cases and 5,918 controls

Previous studies suggest that genetic factors play important roles in the development of colorectal cancer. CYP2E1 T7632A and 9-bp insertion polymorphisms may influence the risk of colorectal cancer, but published results are conflicting. We therefore conducted a meta-analysis comprising 9 case–control studies with 4,592 cases and 5,918 controls. Odds ratios (ORs) with 95 % confidence interval (95 % CI) were used to assess the strength of the associations of CYP2E1 T7632A and 9-bp insertion polymorphisms with colorectal cancer. For CYP2E1 T7632A polymorphism, meta-analysis showed that there was no significant association between the CYP2E1 T7632A polymorphism and colorectal cancer risk under all contrast models (A vs. T: OR?=?1.06, 95 % CI 0.88–1.29, P?=?0.528; AA vs. TT: OR?=?0.85, 95 % CI 0.61–1.19, P?=?0.351; AA/TA vs. TT: OR?=?1.08, 95 % CI 0.87–1.34, P?=?0.484; and AA vs. TT/TA: OR?=?0.87, 95 % CI 0.62–1.21, P?=?0.395). For CYP2E1 96-bp insertion polymorphism, meta-analysis showed that there was a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk under the allele contrast model and the dominant contrast model (for the allele contrast model: OR?=?1.20, 95 % CI 1.06–1.36, P?=?0.005; for the dominant contrast model: OR?=?1.25, 95 % CI 1.07–1.45, P?=?0.005). Subgroup analysis by race suggested that there was an obvious association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk in Asians under the codominant contrast model. In conclusion, our meta-analysis demonstrates that there is a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk, and CYP2E1 9-bp insertion polymorphism is a risk factor for developing colorectal cancer.     

CYP2E1 polymorphisms and colorectal cancer risk: a HuGE systematic review and meta-analysis

Studies investigating the associations between Cytochrome P4502E1 (CYP2E1) polymorphisms and colorectal cancer (CRC) risk report conflicting results. We conducted a meta-analysis to assess the association between CYP2E1 gene Rsa I/Pst I, Dral T/A and 96-bp insertion polymorphisms and CRC susceptibility. Two investigators independently searched the Medline, Embase, CNKI, Wanfang, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for CYP2E1 polymorphisms and CRC were calculated in a fixed-effect model (the Mantel–Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. Ultimately, 12, 5, and 4 studies were found to be eligible for meta-analyses of Rsa I/Pst I, Dral T/A, and 96-bp insertion polymorphisms, respectively. Our analysis suggested that the variant genotype of Rsa I/Pst I were associated with a significantly increased CRC risk (c2/c2 vs. c1/c1, OR?=?1.36, 95 % CI?=?1.04–1.77; recessive model, OR?=?1.35, 95 % CI?=?1.04–1.75). Moreover, similar results were observed between CYP2E1 96-bp insertion polymorphism and CRC risk (dominant model, OR?=?1.25, 95 % CI?=?1.07–1.45), while no association was observed between CYP2E1 Dral T/A polymorphism and CRC susceptibility in any genetic model. No publication bias was found in the present study. This meta-analysis shows that CYP2E1 Rsa I/Pst I and 96-bp insertion polymorphisms may be associated with CRC risk. The CYP2E1 Dral T/A polymorphism was not detected to be related to the risk for CRC.     

CYP2E1PstI/RsaI polymorphism and interaction with tobacco, alcohol and GSTs in gastric cancer susceptibility: A meta-analysis of the literature

Studies investigating the association between cytochrome P450 2E1 (CYP2E1) 5'-flanking region (PstI/RsaI) polymorphism and gastric cancer risk report conflicting results. The rationale for this meta-analysis was to determine whether CYP2E1*2 (c2) variant allele of CYP2E1 increases gastric cancer risk, especially by interacting with smoking, alcohol and other metabolic gene polymorphisms. Two investigators independently searched the Medline and Embase databases. A qualitative scoring of papers was applied to their evaluation. Authors of the identified papers were contacted to obtain data on the mentioned co-exposures. A measurement of the biological interaction among two putative risk factors was estimated by the attributable proportion (AP) due to interaction. We identified 13 case-control studies, which included 2066 gastric cancer cases and 2754 controls. Using the random effects model, we found no association between PstI/RsaI genotype and gastric cancer risk [odds ratio (OR) = 0.97 (95% confidence interval (CI): 0.79-1.18) for c2 allele carriers and OR = 1.36 (95% CI: 0.82-2.25) for c2 homozygotes compared with homozygotes wild-type]. When only high-quality scored studies were considered, a statistically significant increased risk appeared among Asians [OR = 1.50 (95% CI: 1.16-1.94) for c2 carriers and OR = 2.62 (95% CI: 1.23-5.57) for c2 homozygotes]. No interaction was detected between CYP2E1-smoking/alcohol (AP = 0), while an AP of 60% appeared for individuals both c2 homozygotes and glutathione S-transferase M1 (GSTM1) null compared with both homozygotes wild-type. This meta-analysis suggests that the CYP2E1 PstI/RsaI polymorphism may be a risk factor for gastric cancer in Asians, and that a synergic relation among GSTM1 and CYP2E1 may account for a proportion of gastric cancer cases.     

Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6. 6). The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings.     

Updated Meta-analysis of the Association Between CYP2E1 RsaI/PstI Polymorphisms and Lung Cancer Risk in Chinese Population

Background: A number of studies have reported relationships of CYP2E1 RsaI/PstI polymorphisms with susceptibility to lung cancer in Chinese population. However, the epidemiologic results have been conflictive rather than conclusive. The purpose of this study was to address the associations of CYP2E1 RsaI/PstI polymorphisms with lung cancer risk in Chinese population comprehensively. Materials and Methods: Systematic searches were conducted in the PubMed, Science Direct, Elsevier, CNKI and Chinese Biomedical Literature Databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of association. Results: Overall, we observed a decreased lung cancer risk among subjects carrying CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 genotypes (OR=0.76, 95%CI: 0.64-0.90 and OR=0.78, 95%CI: 0.66-0.93, respectively), as compared with subjects carrying the c1/c1 genotype. In subgroup analysis, we observed a decreased lung cancer risk among c1/c2 carriers in hospital-based studies (OR=0.81, 95%CI: 0.68-0.98) and among carriers with c1/c2 and c1/c2+c2/c2 genotypes in population-based studies(OR=0.57, 95%CI: 0.42-0.79 and OR=0.58, 95%CI: 0.43-0.79, respectively), as compared with subjects carrying the c1/c1 genotype. Limiting the analysis to studies with controls in Hardy-Weinberg equilibrium (HWE), we similarly observed a decreased lung cancer risk among c1/c2 and c1/c2+c2/c2 carriers (OR=0.73, 95%CI: 0.60-0.88 and OR=0.73, 95%CI: 0.60-0.88, respectively), as compared with c1/c1. Conclusions: Our results suggested that CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 variants might be a protective factor for developing lung cancer in Chinese population. Further well-designed studies with larger sample size are required to verify our findings.     

Association between CYP2E1 polymorphisms and susceptibility to prostate cancer.

Several genetic alterations have been associated with sporadic prostate cancer (PCa). In this study, the association between RsaI and DraI polymorphisms of CYP2E1 and PCa risk was analysed in a case-control study of 227 individuals using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Regarding DraI polymorphisms, the DD genotype is over-represented in PCa cases when compared with the control group (odds ratio (OR) 2.12; 95% confidence interval (CI) 1.11-4.05; P=0.022). Regarding the RsaI polymorphism, no significant differences were found. The results of this study indicate that DraI polymorphisms of the CYP2E1 gene may be associated with a twofold increased risk for the development of PCa.     

Genetic Polymorphisms of CYP2E1 and GSTM1 in a Thai Population

Cytochrome P450 2E1 and GSTM1 play major roles in metabolic activation and detoxification of many carcinogensand polymorphisms in the encoding genes have been reported to be individually associated with increased susceptibilityto certain cancer. In the present study, we investigated the RsaI, PstI and DraI polymorphisms of the CYP2E1 geneand the null GSTM1 genotype in a Thai population. DNA samples from 485 individuals were analysed by polymerasechain reaction with restriction fragment length (PCR/RFLP). The frequency of RsaI and PstI predominanthomozygous alleles (c1/c1) was 73.2%, heterozygous allele (c1/c2) was 25.6% and rare homozygous allele (c2/c2)was 1.2%. For the DraI polymorphism, the frequency of the predominant allele (DD) was 59.6%, heterozygous (CD)was 40% and rare allele (CC) was 0.4%. The frequency of GSTM1 null genotype was 62.7%. The distribution andfrequencies of these alleles showed different pattern from those found in Caucasian and some other Asian populations.With the large population in this study, we believed that our results are reliable estimates of the frequencies of thepolymorphic CYP2E1 and GSTM1 alleles in Thai population and should provide a base for further epidemiologicalstudies on their links with cancer development.     

Cytochrome P450 2E1 RsaI/PstI and DraI polymorphisms are risk factors for lung cancer in Mongolian and Han population in inner Mongolia

Objective: To explore the relationship between cytochrome P450 2E1 (CYP2E1) RsaI/PstI and DraI polymorphism and lung cancer susceptibility in Mongolian and Han population in Inner Mongolia of China. Methods: CYP2E1 RsaI/PstI and DraI polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 64 lung cancer patients, 150 healthy Mongolian and 150 healthy Han individuals. The distribution of genotype and allele frequencies of CYP2E1 RsaI/PstI and DraI polymorphisms we...     

Genetic polymorphism of cholesterol 7alpha-hydroxylase (CYP7A1) and colorectal adenomas: Self Defense Forces Health Study

Bile acids have long been implicated in colorectal carcinogenesis, but epidemiological evidence is limited. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme producing bile acids from cholesterol. A recent case-control study showed a decreased risk of proximal colon cancer associated with the CC genotype of the CYP7A1 A-203C polymorphism. The present study examined the relationship between the CYP7A1 A-203C polymorphism and colorectal adenoma, which is a well-established precursor lesion of colorectal cancer. The study subjects comprised 446 cases of colorectal adenomas and 914 controls of normal total colonoscopy among men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). The CYP7A1 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Statistical adjustment was made for age, hospital, rank in the SDF, smoking, alcohol use, body mass index, physical activity and parental history of colorectal cancer. The CYP7A1 polymorphism was not measurably related to the overall risk of colorectal adenomas. However, the CC genotype was associated with a decreased risk of proximal colon adenomas, but not of distal colon and rectal adenomas. Adjusted odds ratios of proximal colon adenomas (95% confidence intervals) for the AC and CC genotype versus AA genotype were 0.82 (0.54-1.24) and 0.56 (0.34-0.95), respectively. The findings add to evidence for the role of bile acids in colorectal carcinogenesis. The CC genotype of the CYP7A1 A-203C polymorphism probably renders lower activity of the enzyme synthesizing bile acids.     

Methionine synthase and thymidylate synthase gene polymorphisms and colorectal adenoma risk: the self defense forces study

Folate-mediated one-carbon metabolism has been implicated in colorectal carcinogenesis. We investigated associations of functional genetic polymorphisms of methionine synthase (MTR), MTR reductase (MTRR), and thymidylate synthase (TS) with colorectal adenomas. The study subjects were 455 cases of colorectal adenomas and 1052 controls with no polyp at colonoscopy. Genotypes were determined for MTR A2756G, MTRR A66G and two polymorphisms in the TS gene, 28-bp tandem repeat polymorphism in the promoter enhancer region (TSER) and 6-bp deletion polymorphism at position 1494 in the 3' untranslated region (TS 1494del6). We also examined the alcohol-genotype and gene-gene interactions on adenoma risk. The GG genotype of MTR A2756G was associated with an increased risk of colorectal adenomas; odds ratios for AG and GG versus AA genotype were 0.99 (95% confidence interval 0.78-1.26) and 1.72 (1.04-2.82), respectively. The increase in the risk associated with MTR 2756GG genotype was evident in men with high alcohol consumption (≥30 mL/d), but not in those with low alcohol consumption (interaction P = 0.03). Men who were homozygous for the TSER double-repeat allele had a slightly decreased risk of colorectal adenomas as compared with those homozygous for the TSER triple-repeat allele. Neither MTRR A66G nor TS 1494del6 was associated with colorectal adenomas. There was no measurable interaction either between MTR A2756G and MTRR A66G or between TSER and TS 1494del6. MTR A2756G appears to be associated with colorectal adenoma risk differently according to alcohol consumption. The MTR-catalyzed reaction may play an important role in the development of colorectal adenomas.     

Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer

Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosoamines. We therefore assessed the genotype frequencies of PstI or RsaI CYP2E1 restriction fragment length polymorphisms and another susceptibility marker, mutagen sensitivity, in 137 lung cancer cases (92 African American and 45 Mexican American) and 206 controls (114 African American and 92 Mexican American) identified in a molecular epidemiological study of lung cancer. The CYP2E1 c1/c1 genotype was found in 86.7% of Mexican American cases, 70.6% of Mexican American controls, 89.1% of African American cases and 86.8% of African American controls. By multivariate analysis, this genotype was found to be associated with a 14.0-fold increased risk of lung cancer in Mexican Americans but not in African Americans; a 9.9- fold increased risk of lung cancer in Mexican American former smokers, but not in non-smokers or current smokers; a 15-fold increased risk of lung cancer in Mexican American males, but not in females. Patients with the susceptible genotype appeared to have developed cancer at an earlier age and with lower cigarette pack-year of exposure than did patients with the c1/c2 or c2/c2 genotypes. Stratified analysis suggested a greater than multiplicative interaction between cigarette smoking and CYP2E1 c1/c1 genotype, although not statistically significant. The odds ratios (ORs) for the CYP2E1 c1/c1 genotype, cigarette smoking and both risk factors combined were 1.3, 6.7 and 16.3, respectively. The association between CYP2E1 c1/c1 genotype and pack-years of smoking followed the same pattern. The interaction between mutagen sensitivity and CYP2E1 c1/c1 genotype was especially strong in former smokers (the ORs for the CYP2E1 c1/c1 genotype, mutagen sensitivity and both risk factors combined were 3.9, 5.4 and 23.0, respectively). Therefore, the data suggest that individuals who lack a c2 allele might be at higher risk for developing lung cancer.      

Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high-risk individuals in China.

Esophageal cancer, which is prevalent in China, is believed to be induced by environmental carcinogens such as nitrosamines and other agents. The disproportionate geographical distribution of this cancer among individuals suggests a role for gene-environment interactions in developing the disease. We have shown in our preliminary study that a genetic polymorphism in cytochrome P450 2E1 (CYP2E1) that is known to activate nitrosamines may be a susceptibility factor involved in the early events leading to the development of esophageal cancer (Lin et al., Cancer Epidemiol. Biomark. Prev., 7: 1013-1018, 1998). This relatively larger study was conducted to compare the results with our previous findings. One hundred and fifty cases with esophageal cancer, 146 cases with esophageal dysplasia, and 150 normal controls were residents of Linxian, China, a high-risk area. Genomic DNA samples were assayed for restriction fragment length polymorphisms in the CYP2E1 and GSTP1 loci by PCR amplification followed by digestion with RsaI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was detected by multiplex PCR. The distribution of CYP2E1 c1/c1 allele frequency was found to be significantly different between controls (44.0%) and cases with cancer (71.3%) or cases with dysplasia (70.6%; P < 0.0001). Individuals having the c1/c1 genotype were at a 3.1-fold [95% confidence interval (CI), 2.4-3.9] increased risk of developing dysplasia and a 3.2-fold (95% CI, 2.5-4.1) increased risk of developing squamous cell carcinoma of the esophagus. Although polymorphisms in the GSTT1 and GSTP1 were not significantly different between cases with cancer or cases with dysplasia and controls, the frequency of the GSTM1 non-null (+/+ and +/0) genotypes appeared to be overrepresented in cases with cancer compared with controls (odds ratio, 2.3; 95% CI, 1.8-3.0). Furthermore, a joint effect of the CYP2E1 c1/c1 genotype and GSTM1 non-null genotype on the cancer risk was observed, showing an odds ratio of 8.5 (95% CI, 3.7-19.9). These results demonstrate that CYP2E1 and perhaps GSTM1 are genetic determinants in the development of squamous cell carcinoma of the esophagus.     

细胞色素P450 2E1和谷胱甘肽转硫酶P1基因与食管癌易患性

目的研究与致癌物亚硝胺代谢激活有关的细胞色素Ｐ４５０２Ｅ１基因（ＣＹＰ２Ｅ１）,和与致癌物代谢解毒有关的谷胱甘肽转硫酶Ｐ１基因（ＧＳＴＰ１）多型性与食管癌易患性的关系。方法采用病例－对照分子流行病学方法。以ＰＣＲ－ＲＦＬＰ方法分析食管癌、食管上皮重度增生病例,和与其年龄性别配对的正常对照者（各４５例）ＣＹＰ２Ｅ１和ＧＳＴＰ１的基因型。结果ＧＳＴＰ１基因型在病例和对照者中的分布无显著差别,但ＲｓａＩ识别的ＣＹＰ２Ｅ１基因型,在食管癌、食管上皮重度增生病例及其正常对照者中的分布差别显著。ＣＹＰ２Ｅ１突变型基因频率在正常对照组中为５５．６％,显著高于食管上皮重度增生病例（１７．８％）和食管癌病例（２０．０％;χ２＝２０．８,Ｐ＜０．００１）;携带野生型ＣＹＰ２Ｅ１的个体,发生食管上皮重度增生和食管癌的危险性,比携带变异型ＣＹＰ２Ｅ１的个体各高５倍。结论ＣＹＰ２Ｅ１基因是涉及食管癌变早期过程的遗传易患性因素。     

Polymorphism in CYP1A1 and CYP2E1 genes and susceptibility to leukoplakia in Indian tobacco users

Inter-individual genetic differences may contribute to differences in susceptibility to human diseases triggered by environmental exposures. In this study, we investigated polymorphisms at two sites in the CYP1A1 and three sites in the CYP2E1 genes in 99 leukoplakia patients and 227 controls from one Indian population. The frequencies of genotypes at these polymorphic sites (MspI and Ileu/Val) in the CYP1A1 and (PstI, RsaI and DraI) in the CYP2E1 genes, were similar in patient and control groups. But the combined rare and heterozygous genotypes (CC+CD) at the DraI site in the CYP2E1 gene were over-represented among patients compared with controls (age-adjusted odds ratio (OR)=2.02, 95% confidence interval (CI)=1.21-3.35). Light tobacco smokers (i.e. <21 pack-year) and light tobacco chewers (i.e. <104 chewing-year) with a "rare" C allele at the DraI site had high risk of leukoplakia (OR=2.88, 95% CI=1.16-7.22; OR=2.94, 95% CI=1.15-7.65, respectively). The "mixed tobacco" users with "rare" C allele are more susceptible to the disease than "exclusive" tobacco smokers and chewers. The results indicate that the "rare" C allele at the DraI polymorphic site in CYP2E1 gene may enhance susceptibility to leukoplakia among tobacco users in this population. But the low sample size limited the power to precisely estimate the tobacco-genotype interactions.     

Cytochrome P4502E1 genetic polymorphisms and lung cancer in a Taiwanese population

Cytochrome P4502E1 (CYP2E1) is involved in metabolic activation of carcinogenic nitrosamines, benzene and low molecular weight halogenated hydrocarbons. In this study, we assessed the association between CYP2E1 RsaI and DraI genetic polymorphisms and lung cancer in a Taiwanese population. The RsaI genotype distribution was significantly different between 119 lung cancer patients and 231 non-cancer controls. The homozygote variants of RsaI genotypes were more common in controls (6.9%) than in lung cancer patients (0.8%). The estimated odds ratio (OR) was 0.11 (95% confidence interval (CI), 0.01-0.87). After adjusting for age, sex, and smoking status, the OR was 0.12 (95%, CI, 0.02-0.95). This is the first observation of a positive association between this locus and lung cancer in an Asian population. No significant differences in CYP2E1 DraI genotype distributions were found between cases and controls. The results of this study indicate that CYP2E1 RsaI polymorphism, but not DraI polymorphism, may contribute to the development of lung cancer in Taiwan.     

Comparison of the polymorphic regions of the cytochrome P450 CYP2E1 gene of humans and patas and cynomolgus monkeys.

Cytochrome P450 2E1 (CYP2E1) metabolizes low molecular weight toxicants. CYP2E1 gene polymorphisms have been linked to risk of various cancers and liver disease in humans. Since the patas monkey is a promising model for study of cancer-related alcohol/nitrosamine interactions, we examined CYP2E1 in this monkey for characteristics of two regions that are polymorphic in humans, an RsaI site in the 5' promoter region and a DraI site in intron 6. Another monkey species often used in biomedical research, the cynomolgus monkey, was also examined. Human DNA primers used to amplify a 413 bp segment around the RsaI site also amplified a segment of similar size (409 bp) from DNA of 25 patas monkeys, whereas a product of approximately 800 bp was amplified from DNA of eight cynomolgus monkeys. RsaI did not cut the amplified DNA product from either monkey species. Sequencing revealed that the patas RsaI site was identical to that in humans with the c2c2 CYP2E1 genotype, GTAT. The equivalent cynomolgus sequence, CTAC, has not been observed in humans. Thus, the patas monkey appears to be a useful model for CYP2E1 c2c2 humans, and this genotype, present in 2-25% of humans, may be more primitive than c1c1. For the DraI site, the human primers amplified DNA products similar in size to those from humans, from all patas and cynomolgus monkey DNA samples; none were cut by DraI. Thus, both monkey species appeared to be generally similar to humans of CYP2E1 CC DraI genotype, which is the rarer form of the gene.     

CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people.

CYP1A1, CYP2E1 and GSTM1 polymorphisms were evaluated in Chilean healthy controls and lung cancer patients. In the Chilean healthy group, frequencies of CYP1A1 variant alleles for MspI (m2 or CYP1A1*2A) and ile/val (val or CYP1A1*2B) polymorphisms were 0.25 and 0.33, respectively. Frequencies of variant alleles C (CYP2E1*6) and c2 (CYP2E1*5B) for CYP2E1 were 0.21 and 0.16, respectively and frequency for GSTM1(-) was 0.24. The presence of variant alleles for GSTM1, MspI and Ile/val polymorphisms was more frequent in cases than in controls. However, frequencies for the c2 and C alleles were not significantly different in controls and in cases. The estimated relative risk for lung cancer associated to a single mutated allele in CYP1A1, CYP2E1 or GSTM1 was 2.41 for m2, 1.69 for val, 1.16 for C, 0.71 for c2 and 2.46 for GSTM1(-). The estimated relative risk was higher for individuals carrying combined CYP1A1 and GSTM1 mutated alleles (m2/val, OR=6.28; m2/GSTM1(-), OR=3.56) and lower in individuals carrying CYP1A1 and CYP2E1 mutated alleles (m2/C, OR=1.39; m2/c2, OR=2.00; val/C, OR=1.45; val/c2, OR=0.48; not significant). The OR values considering smoking were 4.37 for m2, 4.05 for val, 3.47 for GSTM1(-), 7.38 for m2/val and 3.68 for m2/GSTM1(-), higher values than those observed without any stratification by smoking. Taken together, these findings suggest that Chilean people carrying single or combined GSTM1 and CYP1A1 polymorphisms could be more susceptible to lung cancer induced by environmental pollutants such as polycyclic aromatic hydrocarbons.     

中国人肺癌易患性与CYP2E1基因多型性相关

目的　研究致癌物代谢酶细胞色素P45 0 2E1基因 (CYP2E1)多型性与肺癌风险的关系。方法　以PCR RFLP方法 ,分析 92例肺癌患者和 137例正常对照者RsaI识别的CYP2E1基因型。结果　c1/c1基因型频率在肺癌病例组为 72 8% ,显著 (P <0 0 1)高于对照组的 5 4 7%。多因素分析表明 ,携带c1/c1的个体发生肺癌的危险性比携带c1/c2和c2 /c2的个体高 2 5倍 (OR 2 5 ,95 %CI 1 8～ 3 8)。分层分析发现 ,c1/c1基因型主要增加肺鳞状细胞癌的危险性 (OR 2 6 ,95 %CI 2 3～ 5 8)。重要的是 ,研究发现CYP2E1c1/c1基因型与吸烟有协同作用。c1/c1基因型或吸烟单因素作用的OR分别为 3 9和 4 1,而二者联合作用的OR为 7 9;当吸烟量 <2 0包 年时 ,c1/c2和c2 /c2基因型的OR为 2 4,而c1/c1基因型的OR为 7 6 ;当吸烟量≥ 2 0包 年时 ,前者的OR为 5 5 ,而后者的OR增加到8 7。结论　CYP2E1c1/c1基因型是中国人肺癌的遗传易患性因素 ,此种基因型与吸烟有协同作用。     

Association between CYP2E1 genetic polymorphisms and lung cancer risk: A meta-analysis

Genetic variations in metabolic genes are thought to modify the metabolic process of carcinogens and are suggested to be related to cancer risk. However, epidemiological results are not always consistent. In this meta-analysis, we assessed reported studies of associations between polymorphisms of CYP2E1 RsaI/PstI and DraI, and the risk of lung cancer. We found decreased lung cancer risk among subjects carrying CYP2E1 RsaI/PstI c1/c2 and c1/c2 + c2/c2 genotype [odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.72–0.89 and OR = 0.82, 95% CI: 0.72–0.93, respectively], using 4436 cases and 6385 controls from 26 studies. We also observed a decreased lung cancer risk among subjects carrying c1/c2 and c1/c2 + c2/c2 genotypes in the Asian population and on the basis of population control in stratified analysis. We found a protective effect of the CYP2E1 DraI CC and CD + CC polymorphisms for lung cancer (OR = 0.58, 95% CI: 0.41–0.81 and OR = 0.84, 95% CI: 0.73–0.96, respectively). The meta-analysis suggests that CYP2E1 RsaI/PstI and DraI polymorphisms may affect the susceptibility of lung cancer, and a study with a larger sample size is needed to further evaluate gene–environment interaction on CYP2E1 polymorphisms and lung cancer risk.