Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Lack of association between EPHX1 polymorphism and esophageal cancer risk: evidence from meta‐analysis

The microsomal epoxide hydrolase 1 (EPHX1) Tyr113His and His139Arg polymorphisms have been reported to be associated with esophageal cancer (EC) risk, yet the results of these previous results have been inconsistent or controversial. The objective of this study was to explore whether the EPHX1 Tyr113His and His139Arg polymorphisms confer risk to EC. The relevant studies were identified through a search of PubMed, Excerpta Medica Database (Embase), Elsevier Science Direct, and Chinese Biomedical Literature Database until May 2013. The association between the EPHX1 Tyr113His and His139Arg polymorphisms and EC risk was pooled by odds ratios (ORs) together with their 95% confidence intervals (95%CIs). A total of eight case–control studies with 1163 EC patients and 1868 controls (seven studies for both Tyr113His and His139Arg polymorphisms, one study only for Tyr113His polymorphism) were eventually identified. We found no association between EPHX1 Tyr113His and His139Arg polymorphisms and EC risk in overall population (For Tyr113His: His vs. Tyr: OR = 1.05, 95%CI = 0.95–1.15, P = 0.379; His/His vs. Tyr/Tyr: OR = 1.04, 95%CI = 0.88–1.22, P = 0.208; His/Tyr vs. Tyr/Tyr: OR = 0.96, 95%CI = 0.80–1.15, P = 0.577; His/His vs. His/Tyr + Tyr/Tyr: OR = 1.10, 95%CI = 0.96–1.26, P = 0.164; His/His + His/Tyr vs. Tyr/Tyr: OR = 1.01, 95%CI = 0.90–1.12, P = 0.543. For His139Arg: Arg vs. His: OR = 1.04, 95%CI = 0.94–1.14, P = 0.465; Arg/Arg vs. His/His: OR = 1.06, 95%CI = 0.91–1.24, P = 0.470; Arg/His vs. His/His: OR = 1.03, 95%CI = 0.91–1.16, P = 0.673; Arg/Arg vs. Arg/His + His/His: OR = 1.04, 95%CI = 0.85–1.27, P = 0.708; Arg/Arg + Arg/His vs. His/His: OR = 1.02, 95%CI = 0.93–1.13, P = 0.617). In subgroup analysis based on ethnicity, significant association has been found in neither EPHX1 Tyr113His nor His139Arg polymorphism. The current meta‐analysis suggests no evidence of association between the EPHX1 polymorphism and EC risk.     

Association between esophageal cancer risk and EPHX1 polymorphisms:A meta-analysis

AIM:To summarize the relationship between p.Tyr113His and p.His139Arg polymorphisms in microsomal epoxide hydrolase(EPHX1)and risk for esophageal cancer(EC).METHODS:The MEDLINE/PubMed and EMBASE databases were searched for studies of the association between EPHX1 polymorphisms and EC risk that were published from the database inception date to April2013.A total of seven case-control studies,including seven on p.Tyr113His(cases,n=1118;controls,n=1823)and six on p.His139Arg(cases,n=861;controls,n=1571),were included in the meta-analysis.After data extraction by two investigators working independently,the meta-analyses were carried out with STATA 11.0 software.Pooled odds ratios and 95%CI were calculated using a fixed-effects model or a random-effects model,as appropriate.RESULTS:The pooled EPHX1 p.Tyr113His polymorphism data showed no significant association with EC in any of the genetic models(OR=1.00,95%CI:0.70-1.48 for Tyr/His vs Tyr/Tyr;OR=1.10,95%CI:0.77-1.57 for His/His vs Tyr/Tyr;OR=1.06,95%CI:0.75-1.49 for a dominant model;OR=1.09,95%CI:0.89-1.34 for a recessive model).Similar results were obtained from the p.His139Arg polymorphism analysis(Arg/His vs His/His:OR=1.02,95%CI:0.84-1.23;Arg/Arg vs His/His:OR=0.96,95%CI:0.60-1.54;OR=1.03,95%CI:0.78-1.37 for the dominant model;OR=0.97,95%CI:0.61-1.56 for the recessive model).Subgroup analyses for ethnicity,subtype of EC,and source of controls(population-based or hospital-based)showed trends that were consistent with the pooled analysis(reported above),with no significant associations found.CONCLUSION:This meta-analysis suggests that the p.Tyr113His and p.His139Arg polymorphisms in EPHX1may not be associated with EC development.     

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.     

异烟肼和利福平联合用药对健康成人原代肝细胞CYP450同工酶1A2和3A4活性的影响

目的明确异烟肼和利福平联合用药对健康成人原代肝细胞CYP450同工酶1A2和3A4活性的影响。方法从健康成人肝脏或肝叶中分离出肝细胞,分为CYP450同工酶1A2和3A4两部分,各分为阴性对照组及药物处理组共15组,放入24孔细胞培养板内,每组6个复孔,原代培养3 d,阴性对照组加入等量的细胞培养液,各药物处理组对应加入临床血药峰浓度范围内的异烟肼(25μmol/L,50μmol/L)、利福平(12.5μmol/L,25μmol/L)或两药联用(CYP1A2:利福平12.5μmol/L加异烟肼50μmol/L,利福平25μmol/L加异烟肼50μmol/L;CYP3A4:利福平12.5μmol/L加异烟肼25μmol/L,利福平25μmol/L加异烟肼25μmol/L,利福平25μmol/L加异烟肼50μmol/L),孵育2 d,再加入CYP450同工酶1A2和3A4的相应底物(非那西丁和睾酮),反应终止后用高效液相仪测量代谢产物(对乙酰氨基酚与6β-羟基睾酮)的峰面积(单位:mAU.m in)代表1A2和3A4的活性。结果(1)单用25μmol/L和50μmol/L浓度异烟肼肝细胞CYP450同工酶1A2的活性分别是(3.33±0.65)、(3.03±0.38)mAU.m in,与阴性对照组的(5.23±0.31)mAU.m in比较差异均有统计学意义(P均<0.01);单用12.5μmol/L浓度利福平肝细胞CYP450同工酶1A2的活性为(6.07±0.55)mAU.m in,与阴性对照组比较差异有统计学意义(P<0.05),单用25μmol/L浓度利福平肝细胞CYP450同工酶1A2的活性为(4.93±0.57)mAU.m in,与阴性对照组比较差异无统计学意义(P>0.05);异烟肼和利福平2种浓度联合配伍,肝细胞CYP450同工酶3A4的活性分别是(3.27±0.96)、(3.97±0.25)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.05)。(2)单用25μmol/L和50μmol/L浓度异烟肼肝细胞CYP450同工酶1A2的活性分别是(5.40±1.35)、(2.63±0.06)mAU.m in,与阴性对照组的(12.53±0.51)mAU.m in比较差异均有统计学意义(P均<0.01);单用12.5和25μmol/L浓度利福平肝细胞CYP450同工酶3A4的活性分别为(165.17±11.47)、(120.20±15.73)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.01);异烟肼和利福平3种浓度联合配伍,肝细胞CYP450同工酶3A4的活性分别是(118.37±8.90)、(77.53±6.91)、(68.73±4.72)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.01),但低于相应浓度单用利福平组(P<0.05或0.01)。结论临床血药峰浓度范围的异烟肼与利福平单用或联用对CYP450同工酶1A2活性影响未达到抑制或诱导水平。临床血药峰浓度范围的异烟肼抑制CYP450同工酶3A4的活性,利福平诱导CYP450同工酶3A4的活性,两药联合仍呈诱导作用。     

Comparison of Levels of Cytochromes P-450, CYP1A2, CYP2E1, and Their Related Monooxygenase Activities in Human Surgical Liver Samples

Hepatic microsomal cytochromes P-450 CYP1A2, and CYP2E1 contents and catalytic activities have been simultaneously investigated in 42 patients undergoing diagnostic liver biopsy. CYP1A2 contents, measured by Western blotting, were correlated with methoxyresorufin-O-demethylation and ethoxyresorufin-O-deethylation ( r = 0.65 and r = 0.66, p < 0.001, respectively). CYP2E1 contents were correlated with 1-butanol oxidation and 6-hydroxylation of chlorzoxazone ( r = 0.75 for both, p < 0.001). CYP1A2 catalytic activities varied by 30- to 40-fold, whereas CYP2E1 activities varied by 6- to 20-fold. In our study, these variations were not related to liver diseases or cancer of the digestive tract nor to alcohol drinking or smoking habits, because patients were alcohol- and tobacco-free for 1 month before the study. Other environmental factors, diet habits, and/or genetic factors could explain the large interindividual variations observed.     

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。     

老年高血压患者血管紧张素转换酶和醛固酮合酶基因多态性与肾素血管紧张素醛固酮的关系

目的分析老年高血压晨峰患者血管紧张素转换酶(ACE)基因I/D、醛固酮合酶(CYP11B2)基因-344C/T多态性与肾素-血管紧张素-醛固酮系统(RAAS)的相关性。方法选择2016年2月~2017年12月云南省第一人民医院老年病科门诊及住院的老年原发性高血压患者200例,根据清晨血压水平分为晨峰增高组58例和非晨峰增高组142例。分析2组患者ACE基因I/D、CYP11B2基因-344C/T多态性和血浆RAAS参数的差异。结果 2组ACE基因型和等位基因频率比较,差异有统计学意义(χ^2=38.020,P=0.000;χ^2=42.040,P=0.000)。2组CYP11B2基因型和等位基因频率比较,差异无统计学意义(χ^2=0.261,P=0.878;χ^2=0.198,P=0.656)。晨峰增高组DD+TC、DD+TT基因型比例明显高于非晨峰增高组,差异有统计学意义(22.4%vs 3.5%,12.1%vs 2.1%,P<0.01);晨峰增高组II+TT、II+TC基因型比例明显低于非晨峰增高组,差异有统计学意义(13.8%vs 29.6%,P<0.05;5.2%vs 22.5%,P<0.01)。晨峰增高组血浆肾素、血管紧张素Ⅱ和醛固酮水平明显高于非晨峰增高组,差异有统计学意义(P<0.05,P<0.01)。logistic回归分析显示,DD+CC、DD+TC、DD+TT、肾素、血管紧张素Ⅱ为血压晨峰的重要影响因素(OR=8.084,95%CI:1.261~51.832,P=0.027;OR=14.459,95%CI:3.804~54.964,P=0.000;OR=9.753,95%CI:2.255~42.181,P=0.002;OR=1.816,95%CI:1.258~2.620,P=0.001;OR=0.634,95%CI:0.437~0.921,P=0.017)。结论 ACE基因DD型、肾素、血管紧张素Ⅱ是血压晨峰形成的主要影响因素。     

Interaction models of CYP1A1, GSTM1 polymorphisms and tobacco smoking in intestinal gastric cancer

AIM: To explore the interaction models of the cytochrome P-450 (CYP) 1A1 Val variant and glutathione S-transferase (GST) M1 null polymorphisms with tobacco smoking in the occurrence of intestinal gastric cancer. METHODS: A community-based case-control study was conducted in Yangzhong. Subjects included 114 intestinal types of gastric cancer with endoscopic and pathological diagnosis during January 1997 and December 1998, and 693 controls selected from their spouse, siblings or siblings-in-law who had no history of digestive system cancer. Logistic regression was used to estimate the interaction models. RESULTS: The frequency of the CYP1A1 Val variant allele in cases did not differ from that in controls. The OR of GSTM1 null genotype was 2.0 (95% confidence interval (95%CI): 1.2-3.1, P<0.01). It showed a significant type 2 form of interaction model when both CYP1A1 Val variant allele and former tobacco smoking existed (i.e., among the multiplicative effects, the disease risk is increased by the tobacco exposure alone but not by the CYP1A1 variant alone). The interaction index gamma was 2.8, and OR(eg) (95%CI) was 5.0 (1.9-13.4). GSTM1 null genotype and former tobacco smoking were significant in a type 4 interaction model (i.e., the disease risk is increased by GSTM1 null genotype or tobacco exposure alone among the multiplicative effects). The interaction index gamma and OR(eg) (95%CI) were 3.4 and 8.4 (3.4-20.9), respectively. CONCLUSION: Different interaction models of CYP1A1 Val variant allele and GSTM1 null genotype with tobacco smoking will contribute to understanding carcinogenic mechanism, but there is a need to further investigate in larger scale studies.     

Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation

BACKGROUND AND OBJECTIVES: Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding. DESIGN AND METHODS: CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding. RESULTS: Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol (70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS). INTERPRETATION AND CONCLUSIONS: CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.     

CYP2J2基因和EPHX2基因多态性与肺癌易感性研究

目的探讨CYP2J2基因启动子区G-50T多态性和EPHX2基因G860A多态性与肺癌发生的关系。方法经病理检查确诊为肺癌患者150例（肺癌组）,300名本院健康体检者作为对照组,检测其CYP2J2基因启动子区G-50T多态性和EPHX2基因G860A多态性,并进行统计学分析。结果肺癌组和对照组比较,CYP2J2启动子区G-50T多态性差异无统计学意义,而肺癌组患者EPHX2 860G等位基因频率显著高于对照组人群（96％比78．3％,P〈0．01）,多元回归分析方法显示,肺癌的发生与EPHX2 G860A多态性显著相关（校正OR值=0．164,95％CI 0．079～0．342,P〈0．001）。结论EPHX2 G860A多态件与肺痛密切相关．可作为肺癌高毹患者的预涮指标．     

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   

CYP2J2基因和EPHX2基因多态性与缺血性脑卒中的遗传易感性

目的 研究我国汉族人群细胞色素P450表氧化酶2J2(CYP2J2),可溶性环氧化物水解酶2(EPHX2)基因多态性与缺血性脑卒中的关系.方法 选择200例缺血性脑卒中患者和350例健康人群,采用PCR-RFLP技术分析两个基因CYP2J2 G-50T,EPHX2 G860A多态性的基因型.结果 仅EPHX2 860A等位基因频率在缺血性脑卒中组与对照组比较有显著性差异.多元Logistic回归分析表明,携带EPHX2 860A等位基因的人群患缺血性脑卒中相对风险率下降50%(OR=0.5).当个体同时携带CYP2J2-50GG和EPHX2 860A (A 示A等位基因)联合基因型时,其患缺血性脑卒中相对风险率下降53.9%(OR=0.461).结论 虽然EPHX2 860A等位基因与缺血性脑卒中有相关性并且为缺血性脑卒中一个独立的保护因子,但联合基因型CYP2J2-50GG/EPHX2 860A 的协同作用对缺血性脑卒中有更强的保护作用.     

GSTM1, GSTT1, GSTP1 and CYPIA1 genetic polymorphisms and susceptibility to esophageal cancer in a French population： Different pattern of squamous cell carcinoma and adenocarcinoma

AIM: To evaluate the association between CYPIA1 and GSTs genetic polymorphisms and susceptibility to esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinorna (ADC) in a high risk area of northwest of France.METHODS: A case-control study was conducted to investigate the genetic polymorphisms of these enzymes (CYPIAI*2C and GSTP1 exon 7 Val alleles, GSTM1 *2/*2 and GSl-l-l*2/*2 null genotypes). A total of 79 esophagealcancer cases and 130 controls were recruited. RESULTS: GSTM2*2/*2 and CYP1A1*1A/*2C genotype frequencies were higher among squamous cell cardnomas at a level close to statistical significance (OR = 1.83, 95% CI0.88-3.83, P= 0.11; OR = 3.03, 95% CI 0.93-9.90, P= 0.07,respectively). For GSTP1 polymorphism, no difference wasfound between controls and cases, whatever their histological status. Lower frequency of GST/-1 deletion was observed in ADC group compared to controls with a statistically significant difference (OR=13.31, 95% CI 1.66-106.92, P&lt;0.01).CONCLUSION: In SCC, our results are consistent with the strong association of this kind of turnout with tobacco exposure. In ADC, our results suggest 3 distinct hypotheses:(1) activation of exogenous procarcinogens, such as small halogenated compounds by GSTTI‘, (2) contribution of GSTT1 to the inflammatory response of esophageal mucosa, which is known to be a strong risk factor for ADC,possibly through leukotriene synthesis; (3) higher sensitivity to the inflammatory process associated with intracellular depletion of glutathione.     

Cytochrome P450 2E1 genetic polymorphism and gastric cancer in Changle, Fujian Province

AIM:Genetic polymorphism in enzymes of carcinogenmetabolism has been found to have the influence on thesusceptibility to cancer.Cytochrome P450 2E1(CYP2 E1)isconsidered to play an important role in the metabolicactivation of procarcinogens such as N-nitrosoamines andlow molecular weight organic compounds.The purpose ofthis study is to determine whether CYP450 2E1polymorphisms are associated with risks of gastric cancer.METHODS:We conducted a population based case-controlstudy in Changle county,Fujian Province,a high-riskregion of gastric cancer in China.Ninety-one incidentgastric cancer patients and ninety-four healthy controls wereincluded in our study.Datas including demographiccharacteristcs,diet intake,and alcohol and tobaccoconsumption of indivduais in our study were completad by astandardized questionnaire.PCR-RFLP revealed threegenotypes:heterozyote(C1/C2)and two homozygotes(C1/C1 and C2/C2)in CYP2E1.RESULTS:The frequency of variant genotypes(C1/C2 andC2/C2)in gastric cancer cases and controls was 36.3% and24.5%,respectively.The rare homozygous C2/C2 genotypewas found in 6 indivduals in gastric cancer group(6.6%),whereas there was only one in the control group(1.1%).However,there was no statistically significan differencebetween,the two groups(two-tailed Rsher's exact test,P=0.066).Indlvduals in gastric cancer group were more likelyto carry genotype C1/C2(odds ratio,OR=1.50)and C2/C2(OR=7.34)than indlvduals in control group(x~2=4.597,fortrend P=0.032).The frequencies of genotypes with the C2allele(C1/C2 and C2/C2 genotypes)were compared withthose of genotypes without C2 alleie(C1/C1 genotype)among indlvduals in gastric cancer group and control groupaccording to the pattem of gastric cancer risk factors.Theresults show that indlvduals who exposed to these gastriccancer risk factors and carry the C2 allele seemed to have ahigher risk of developing gastric cancer.CONCLUSION:Polymorphism of CYP2E1 gene may havesome effct in the development of gastric cancer in Changle county,Fujian Province.     

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.     

醛固酮合成酶基因多态性与小动脉顺应性的研究

目的探讨醛固酮合成酶（CYP11B2）基因-344C／T多态性与小动脉顺应性（C2）的关系及其临床意义。方法（1）用CVProfilorDO-2020动脉脉搏分析仪测量大小动脉顺应性,共224例,其中C2异常组123例,对照组101例。（2）用多聚酶链反应-限制性片段长度多态性分析方法检测CYP11B2基因-344C／T多态性。结果（1）C2异常组TT基因型、T等位基因频率均高于对照组,但差异无统计学意义（55．3％比41．6％,P〉0．05,75．6％比66．8％,P〉0．05）。（2）CC型与CT型合并分析,显示C2异常组TT型频率显著高于对照组（30．3％比18．8％,P〈0．05）。（3）协方差分析显示,与CT／CC型比较,TT型者C2显著降低。（4）Logistic回归分析表明,TT型是导致C2减退重要的基因型（P=0．043,OR=1．9395％ CI1．02～3．63）。结论CYP11B2基因-344C／T多态性与小动脉顺应性C2密切相关,TT型是C2减退的敏感基因型。     

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer

Purpose As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN). Methods A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI). Results SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93–6.35) and OR = 6.47 (95%CI: 2.92–14.35) for 19–30 g/day and >30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88–6.41) and OR = 7.65 (95%CI: 4.20–13.90) for 1–25 and >25 pack-years of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53–3.92). No differences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene–gene and gene–environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40–0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10–0.72) resulted forever smokers with low fruit and vegetables consumption. Conclusions Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype.     

细胞色素P4502C19基因多态性对介入术后服用氯吡格雷冠心病患者临床预后的影响

目的 探讨细胞色素P450(CYP)2C19 681G>A基因多态性对经皮冠状动脉介入治疗(PCI)后服用氯吡格雷冠心病患者临床预后的影响.方法 入选2009年1月1日至8月31日拟行PCI,并在术后服用氯吡格雷12个月的冠心病患者267例.采用MassARRAY时间飞行质谱检测入选患者CYP2C19 681G>A位点.按基因型不同,将患者分为CYP2C19*1/*1组 (n=130)和CYP2C19*2携带组(n=137).观察两组患者术后1年心绞痛复发、紧急血运重建术、急性心肌梗死、支架内血栓形成和死亡的发生情况.结果 两组患者的临床基本资料差异无统计学意义(P>0.05).PCI术后1年,CYP2C19*2携带组紧急血运重建术和联合终点事件的发生率均高于CYP2C19*1/*1组 (分别为7.3%比1.5%和8.0%比2.3%,P均<0.05).两组患者心绞痛复发、急性心肌梗死、支架内血栓形成和死亡的发生率差异均无统计学意义(P均>0.05).CYP2C19*2携带组随访1年的累积联合终点事件发生风险是CYP2C19*1/*1组的3.59倍(HR=3.59,95%CI:1.02～12.87,P<0.05).结论 CYP2C19 681G>A基因多态性可能是影响PCI术后服用氯吡格雷冠心病患者临床预后的因素.

Abstract：

Objective To investigate the impact of cytochrome P450 (CYP) 2C19 681G>A polymorphism on long-term prognosis of clopidogrel-treated Chinese patients after percutaneous coronary intervention (PCI).Methods Between January 1, 2009 and August 31,2009, 267 patients with coronary heart disease who received PCI and treated with clopidogrel for 12 months were enrolled. CYP2C19*2 was detected by MALDI-TOF MS and patients were grouped into CYP2C19*1/*1(n=130) and CYP2C19*2 carriers group (n=137). Follow-up was 12 months. The primary endpoint was angina recurrence, urgent coronary revascularization, acute myocardial infarction, stent thrombosis, death and the combined end points. Results Baseline data were similar between two groups (P>0.05).Urgent coronary revascularization and the combined end points occurred more frequently in CYP2C19*2 carriers than in CYP2C19*1/*1 patients (7.3% vs. 1.5% and 8.0% vs. 2.3% respectively,all P<0.05). But incidence of angina recurrence, acute myocardial infarction, stent thrombosis and death was similar between two groups (all P>0.05).Hazard risk of 1 year cumulative survival of CYP2C19*2 carriers group was significantly higher than CYP2C19*1/*1 group after PCI (HR=3.59, 95%CI: 1.02-12.87, P<0.05). Conclusion CYP2C19 681G>A polymorphism is a determinant of prognosis in coronary heart disease patients receiving chronic clopidogrel treatment after PCI.