代谢酶基因多态性、外暴露因素及其交互作用与肝癌易感性关系的研究
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摘要
目的:分析I相代谢酶基因(CYP2E1、CYP1A1)和II相代谢酶基因(GSTM1、EPHX1)的多态性与广西西南部地区人群中肝癌易感性的关系,并从基因-基因、基因-外暴露因素的角度,探讨代谢酶基因间以及各代谢酶基因与外暴露因素的交互作用效应,为肝癌的筛查及早期诊断寻找相关分子标志物,以及为有针对性地开展行为干预和化学预防提供一些线索。
方法:采用病例-对照研究设计,包括肝癌病例102例,正常对照102例,研究对象均来自广西西南部地区,运用PCR和PCR-RFLP等实验技术,检测代谢酶基因的多态性;采用统计学软件SPSS16.0,用χ~2检验分析对照组中各代谢酶基因型的分布是否符合Hardy-Weinberg遗传平衡定律和CYP2E1、CYP1A1、EPHX1和GSTM1的基因型在病例组和对照组的分布及其与肝癌风险关系,用比值比(odds ratio,OR)及其95%可信区间(confidence intervals,CI)来表示相对危险度;采用基于相乘模型的叉生分析法分析基因-基因、基因-外暴露因素的交互作用。
结果: 1、一般资料:病例组和对照组的年龄、性别、民族等分布差异无统计学意义(P>0.05)。
2、外暴露因素的分布:饮酒、HBsAg携带情况在病例组和对照组的分布均有统计学意义(P<0.05),其OR(95%CI)分别为2.08(1.181～3.663)、20.833(9.882～43.922);而吸烟在肝癌病例组和对照组的分布差异没有统计学意义(P=0.093),其OR(95%CI)为1.606(0.923～2.792)。
3、Hardy-Weinberg平衡检验:对照组中CYP2E1、CYP1A1和EPHX1等位基因频率分布均符合Hardy-Weinberg遗传平衡定律(P>0.05)。
4、代谢酶基因多态的分布情况:
(1)GSTM1 null、no-null基因型频率在肝癌病例组分别为52%、48%,在对照组分别为41.2%、58.8%,两组的分布差异没有统计学意义(χ~2=2.384,P=0.123)。
(2)CYP2E1经RsaI酶切c1/c1、c1/c2、c2/c2基因型频率在肝癌病例组分别为61.8%、30.4%、7.8%,在对照组分别为55.9%、41.2%、2.9%,两组的分布差异没有统计学意义(χ~2=4.322,P=0.115)。
(3)CYP1A1经MspI酶切所得IIe/IIe、IIe/Val、Val/Val基因型频率在肝癌病例组分别为34.3%、46.1%、19.6%,在对照组分别为43.1%、45.1%、11.8%,两组的分布差异没有统计学意义(χ~2=3.036,P=0.219)。
(4)EPHX1经RsaI酶切所得His/His、His/Arg、Arg/Arg基因型频率在肝癌病例组分别为72.5%、25.5%、2%,在对照组分别为62.7%、37%、1%,两组的分布差异没有统计学意义(χ~2=2.966,P=0.226)。
经校正后,各OR有增大趋势,但是差异均仍无统计学意义(P>0.05)。
5、基因-基因的交互作用效应:
(1)两两基因的联合:GSTM1与CYP2E1的联合、CYP2E1与CYP1A1的联合,交互作用均有统计学意义(P_(交互)分别为0.005和0.04),且均为协同作用(I>1)。其余基因的两两联合对肝癌的风险可能不存在统计学意义(P_(交互)>0.05)。
(2)三个基因的联合: GSTMI、CYP2E1、CYP1A1三者联合,GSTMI、CYP2E1、EPHX1三者联合,EPHX1、CYP2E1、CYP1A1三者联合,存在有统计学意义的交互作用(P_(交互)分别为0.001、0.016和0.032);GSTMI、CYP1A1、EPHX1三者联合可能不存在有统计学意义的交互作用(P_(交互)=0.066),但是联合后的OR均有增大趋势。
(3)四个基因的联合:把GSTM1null基因型、CYP2E1c1/c1基因型、CYP1A1IIe/Val或Val/Val突变基因型、EPHX1 His/His基因型视为危险因素,随着暴露因素的增加,个体患肝癌风险增大,差异有统计学意义(χ~2=13.064,P=0);携带GSTM1null基因型、CYP2E1c1/c1基因型、CYP1A1突变基因型且EPHX1 His/His基因型患肝癌的危险性是携带GSTM1 no-null基因型、EPHX1 His/Arg或Arg/Arg、CYP2E1c1/c2或c2/c2且CYP1A1 IIe/ IIe型的6.876倍,其95%CI为1.104～42.798。
6、基因-外暴露因素的交互作用效应
(1)饮酒联合GSTM1、CYP2E1、CYP1A1、EPHX1各代谢酶基因多态对肝癌的发生均存在明显的协同作用(P_(交互)均小于0.05,I均大于1)。
(2)吸烟联合EPHX1基因多态对肝癌有明显的协同作用(P_(交互)=0.029,I>1);吸烟与CYP1A1基因多态的联合对肝癌的发生可能不存在有统计学意义的交互作用(P_(交互)=0.227),而吸烟联合GSTM1、CYP2E1各基因多态与肝癌交互作用的P_(交互)处于临界值。
(3)HBsAg与GSTM1、CYP1A1、EPHX1各代谢酶基因多态对肝癌的发生均存在有明显的协同作用(P_(交互)均小于0.05,I均大于1),而HBsAg联合CYP2E1基因多态对肝癌可能不存在有统计学意义的交互作用(P_(交互)=0.305)。
结论:GSTM1、CYP2E1、CYP1A1、EPHX1单一基因的多态性对肝癌可能没有效应或作用微弱,但是两种或两种以上基因多态联合或与外暴露因素的联合作用,患肝癌的风险性增强,而不同基因间的联合以及不同基因与外暴露因素的联合作用对肝癌的风险又不尽相同,因此,在探讨基因的易感作用时,应考虑基因-基因、基因-外暴露因素的关系,在肝癌筛查和防治工作中,应联合考虑相关分子标志物以及有针对性地开展行为干预和化学预防。
Objective: To study the relationship between genetic polymorphisms of phaseⅠ(CYP2E1、CYP1A1) and phaseⅡ(GSTM1、EPHX1) metabolizing enzymes and susceptibility to primary hepatocellular carcinoma (PHC) in southwest Guangxi province, and to find out whether there is gene-gene or gene-external exposure factors interaction between them. So as to provide a new route for screening and early diagnosis and making the integrated preventive measures for PHC in Guangxi Province.
Methods: A case-control study was conducted, which included 102 Patients with PHC and 102 normal controls in southwest GuangXi subjects. Genetic polymorphisms of phaseⅠ(CYP2E1, CYP1A1) and phaseⅡ(GSTM1, EPHX1) were determined by Polymerase chain reaction(PCR) and Polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). Statistics analysis adopt SPSS16.0 statistical package. Departure from Hardy-Weinberg Equilibrium (HWE) for polymorphism genotype in controls was tested by Chi-square test. The distribution differences of polymorphisms of CYP2E1, CYP1A1, GSTM1, EPHX1 and related risk between the case group and control group were analyzed by chi-square test. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) were used to evaluate associations between polymorphism genotype and PHC risk. Based on the multiplication model of crossover analysis and Logistic regression were used to analyze the relationship of gene-gene, gene-external exposure factors interaction. All statistical tests were two-sided withαis 0.05.
Results: 1. There were no statistically differences in the distribution of age, sex , nationality between cases and controls, respectively (P>0.05).
2. Hepatitis B infection, drinking showed significant difference between cases and controls (P < 0.05), OR(95%CI) were 2.08(1.181～3.663), 20.833(9.882～43.922), respectively. There was no statistically differences in the distribution of smoking between two groups (P>0.05).
3. The genotype frequency distribution of CYP2E1, CYP1A1, EPHX1 were in accordance with the Hardy-Weinberg Equilibrium among the controls (P>0.05).
4.(1) As for CYP2E1 genotype, frequencies of c1/c1, c1/c2, c2/c2 genotype were 61.8%, 30.4%, 7.8% in case group, 55.9%, 41.2%, 2.9% in control group respectively . The difference were no significant between two groups (χ~2=4.322,P=0.115).
(2) As for CYP1A1 genotype, frequencies of IIe/IIe, IIe/Val, Val/Val genotype were 34.3%, 46.1%, 19.6% in case group, 43.1%, 45.1%, 11.8% in control group respectively. The difference were no significant between two groups (χ~2=3.036,P=0.219).
(3) As for GSTM1 genotype, frequencies of null, no-null genotype were 52%, 48% in case group, 41.2%, 58.8% in control group respectively. The difference were no significant between two groups (χ~2=2.384,P=0.123).
(4) The frequencies of polymorphism genotype of His/His, His/Arg, Arg/Arg of EPHX1 gene in patients with PHC were 72.5%, 25.5%, 2% respectively, which in the control group were 62.7%, 37%, 1% respectively. The difference were no significant between two groups(χ~2=2.966,P=0.226).
5. Gene-gene interaction analytical results:
(1) When combination both of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype were analyzed, combination of the GSTM1, CYP2E1 and the CYP2E1, CYP1A1 were associated with the risk of PHC.
(2) When combination every three of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype were analyzed, except the combination of GSTMI, CYP1A1, EPHX1 might be not associated with the susceptibility of PHC, others were associated with the susceptibility of PHC.
(3) When combination of polymorphism of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype was analyzed, the risk of PHC was increased. And the risk of suffering PHC in individuals with CYP2E1c1/c1, CYP1A1(IIe/Val or Val/Val), EPHX1His/His, GSTM1null was 6.876 fold increase than that without any of them (95%CI was 1.104-42.789).
6. Gene-external exposure factors interaction analytical results:
(1) The combination of drinking and a single gene of CYP2E1, CYP1A1, GSTM1, EPHX1 are associated with the risk of PHC.
(2) There was synergistic action between smoking and EPHX1 genotype on the risk of PHC (P=0.029). Smoking combined with CYP1A1 genotype might no synergistic action on the susceptibility of PHC (P=0.227). And no obvious interaction was observed in smoking combined with other genotype.
(3) Interaction existed between CYP1A1 or GSTM1 or EPHX1 genotype and hepatitis B infection. Hepatitis B infection combined with CYP2E1 genotype might no synergistic action on the susceptibility of PHC (P=0.305).
Conclusions:The Polymorphism of a single gene of CYP2E1, CYP1A1, GSTM1, EPHX1 might be not associated with the susceptibility of PHC, but when they combined with each other or combined with smoking or drinking; the risks of PHC were increased. These results suggest that gene-gene or gene-external exposure factors interaction play an importance role in the susceptibility of PHC, in addition, it necessary to take targeted preventive measures for PHC in Guangxi Province.
方法:采用病例-对照研究设计,包括肝癌病例102例,正常对照102例,研究对象均来自广西西南部地区,运用PCR和PCR-RFLP等实验技术,检测代谢酶基因的多态性;采用统计学软件SPSS16.0,用χ~2检验分析对照组中各代谢酶基因型的分布是否符合Hardy-Weinberg遗传平衡定律和CYP2E1、CYP1A1、EPHX1和GSTM1的基因型在病例组和对照组的分布及其与肝癌风险关系,用比值比(odds ratio,OR)及其95%可信区间(confidence intervals,CI)来表示相对危险度;采用基于相乘模型的叉生分析法分析基因-基因、基因-外暴露因素的交互作用。
结果: 1、一般资料:病例组和对照组的年龄、性别、民族等分布差异无统计学意义(P>0.05)。
2、外暴露因素的分布:饮酒、HBsAg携带情况在病例组和对照组的分布均有统计学意义(P<0.05),其OR(95%CI)分别为2.08(1.181～3.663)、20.833(9.882～43.922);而吸烟在肝癌病例组和对照组的分布差异没有统计学意义(P=0.093),其OR(95%CI)为1.606(0.923～2.792)。
3、Hardy-Weinberg平衡检验:对照组中CYP2E1、CYP1A1和EPHX1等位基因频率分布均符合Hardy-Weinberg遗传平衡定律(P>0.05)。
4、代谢酶基因多态的分布情况:
(1)GSTM1 null、no-null基因型频率在肝癌病例组分别为52%、48%,在对照组分别为41.2%、58.8%,两组的分布差异没有统计学意义(χ~2=2.384,P=0.123)。
(2)CYP2E1经RsaI酶切c1/c1、c1/c2、c2/c2基因型频率在肝癌病例组分别为61.8%、30.4%、7.8%,在对照组分别为55.9%、41.2%、2.9%,两组的分布差异没有统计学意义(χ~2=4.322,P=0.115)。
(3)CYP1A1经MspI酶切所得IIe/IIe、IIe/Val、Val/Val基因型频率在肝癌病例组分别为34.3%、46.1%、19.6%,在对照组分别为43.1%、45.1%、11.8%,两组的分布差异没有统计学意义(χ~2=3.036,P=0.219)。
(4)EPHX1经RsaI酶切所得His/His、His/Arg、Arg/Arg基因型频率在肝癌病例组分别为72.5%、25.5%、2%,在对照组分别为62.7%、37%、1%,两组的分布差异没有统计学意义(χ~2=2.966,P=0.226)。
经校正后,各OR有增大趋势,但是差异均仍无统计学意义(P>0.05)。
5、基因-基因的交互作用效应:
(1)两两基因的联合:GSTM1与CYP2E1的联合、CYP2E1与CYP1A1的联合,交互作用均有统计学意义(P_(交互)分别为0.005和0.04),且均为协同作用(I>1)。其余基因的两两联合对肝癌的风险可能不存在统计学意义(P_(交互)>0.05)。
(2)三个基因的联合: GSTMI、CYP2E1、CYP1A1三者联合,GSTMI、CYP2E1、EPHX1三者联合,EPHX1、CYP2E1、CYP1A1三者联合,存在有统计学意义的交互作用(P_(交互)分别为0.001、0.016和0.032);GSTMI、CYP1A1、EPHX1三者联合可能不存在有统计学意义的交互作用(P_(交互)=0.066),但是联合后的OR均有增大趋势。
(3)四个基因的联合:把GSTM1null基因型、CYP2E1c1/c1基因型、CYP1A1IIe/Val或Val/Val突变基因型、EPHX1 His/His基因型视为危险因素,随着暴露因素的增加,个体患肝癌风险增大,差异有统计学意义(χ~2=13.064,P=0);携带GSTM1null基因型、CYP2E1c1/c1基因型、CYP1A1突变基因型且EPHX1 His/His基因型患肝癌的危险性是携带GSTM1 no-null基因型、EPHX1 His/Arg或Arg/Arg、CYP2E1c1/c2或c2/c2且CYP1A1 IIe/ IIe型的6.876倍,其95%CI为1.104～42.798。
6、基因-外暴露因素的交互作用效应
(1)饮酒联合GSTM1、CYP2E1、CYP1A1、EPHX1各代谢酶基因多态对肝癌的发生均存在明显的协同作用(P_(交互)均小于0.05,I均大于1)。
(2)吸烟联合EPHX1基因多态对肝癌有明显的协同作用(P_(交互)=0.029,I>1);吸烟与CYP1A1基因多态的联合对肝癌的发生可能不存在有统计学意义的交互作用(P_(交互)=0.227),而吸烟联合GSTM1、CYP2E1各基因多态与肝癌交互作用的P_(交互)处于临界值。
(3)HBsAg与GSTM1、CYP1A1、EPHX1各代谢酶基因多态对肝癌的发生均存在有明显的协同作用(P_(交互)均小于0.05,I均大于1),而HBsAg联合CYP2E1基因多态对肝癌可能不存在有统计学意义的交互作用(P_(交互)=0.305)。
结论:GSTM1、CYP2E1、CYP1A1、EPHX1单一基因的多态性对肝癌可能没有效应或作用微弱,但是两种或两种以上基因多态联合或与外暴露因素的联合作用,患肝癌的风险性增强,而不同基因间的联合以及不同基因与外暴露因素的联合作用对肝癌的风险又不尽相同,因此,在探讨基因的易感作用时,应考虑基因-基因、基因-外暴露因素的关系,在肝癌筛查和防治工作中,应联合考虑相关分子标志物以及有针对性地开展行为干预和化学预防。
Objective: To study the relationship between genetic polymorphisms of phaseⅠ(CYP2E1、CYP1A1) and phaseⅡ(GSTM1、EPHX1) metabolizing enzymes and susceptibility to primary hepatocellular carcinoma (PHC) in southwest Guangxi province, and to find out whether there is gene-gene or gene-external exposure factors interaction between them. So as to provide a new route for screening and early diagnosis and making the integrated preventive measures for PHC in Guangxi Province.
Methods: A case-control study was conducted, which included 102 Patients with PHC and 102 normal controls in southwest GuangXi subjects. Genetic polymorphisms of phaseⅠ(CYP2E1, CYP1A1) and phaseⅡ(GSTM1, EPHX1) were determined by Polymerase chain reaction(PCR) and Polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). Statistics analysis adopt SPSS16.0 statistical package. Departure from Hardy-Weinberg Equilibrium (HWE) for polymorphism genotype in controls was tested by Chi-square test. The distribution differences of polymorphisms of CYP2E1, CYP1A1, GSTM1, EPHX1 and related risk between the case group and control group were analyzed by chi-square test. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) were used to evaluate associations between polymorphism genotype and PHC risk. Based on the multiplication model of crossover analysis and Logistic regression were used to analyze the relationship of gene-gene, gene-external exposure factors interaction. All statistical tests were two-sided withαis 0.05.
Results: 1. There were no statistically differences in the distribution of age, sex , nationality between cases and controls, respectively (P>0.05).
2. Hepatitis B infection, drinking showed significant difference between cases and controls (P < 0.05), OR(95%CI) were 2.08(1.181～3.663), 20.833(9.882～43.922), respectively. There was no statistically differences in the distribution of smoking between two groups (P>0.05).
3. The genotype frequency distribution of CYP2E1, CYP1A1, EPHX1 were in accordance with the Hardy-Weinberg Equilibrium among the controls (P>0.05).
4.(1) As for CYP2E1 genotype, frequencies of c1/c1, c1/c2, c2/c2 genotype were 61.8%, 30.4%, 7.8% in case group, 55.9%, 41.2%, 2.9% in control group respectively . The difference were no significant between two groups (χ~2=4.322,P=0.115).
(2) As for CYP1A1 genotype, frequencies of IIe/IIe, IIe/Val, Val/Val genotype were 34.3%, 46.1%, 19.6% in case group, 43.1%, 45.1%, 11.8% in control group respectively. The difference were no significant between two groups (χ~2=3.036,P=0.219).
(3) As for GSTM1 genotype, frequencies of null, no-null genotype were 52%, 48% in case group, 41.2%, 58.8% in control group respectively. The difference were no significant between two groups (χ~2=2.384,P=0.123).
(4) The frequencies of polymorphism genotype of His/His, His/Arg, Arg/Arg of EPHX1 gene in patients with PHC were 72.5%, 25.5%, 2% respectively, which in the control group were 62.7%, 37%, 1% respectively. The difference were no significant between two groups(χ~2=2.966,P=0.226).
5. Gene-gene interaction analytical results:
(1) When combination both of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype were analyzed, combination of the GSTM1, CYP2E1 and the CYP2E1, CYP1A1 were associated with the risk of PHC.
(2) When combination every three of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype were analyzed, except the combination of GSTMI, CYP1A1, EPHX1 might be not associated with the susceptibility of PHC, others were associated with the susceptibility of PHC.
(3) When combination of polymorphism of CYP2E1, CYP1A1, GSTM1, EPHX1 genotype was analyzed, the risk of PHC was increased. And the risk of suffering PHC in individuals with CYP2E1c1/c1, CYP1A1(IIe/Val or Val/Val), EPHX1His/His, GSTM1null was 6.876 fold increase than that without any of them (95%CI was 1.104-42.789).
6. Gene-external exposure factors interaction analytical results:
(1) The combination of drinking and a single gene of CYP2E1, CYP1A1, GSTM1, EPHX1 are associated with the risk of PHC.
(2) There was synergistic action between smoking and EPHX1 genotype on the risk of PHC (P=0.029). Smoking combined with CYP1A1 genotype might no synergistic action on the susceptibility of PHC (P=0.227). And no obvious interaction was observed in smoking combined with other genotype.
(3) Interaction existed between CYP1A1 or GSTM1 or EPHX1 genotype and hepatitis B infection. Hepatitis B infection combined with CYP2E1 genotype might no synergistic action on the susceptibility of PHC (P=0.305).
Conclusions:The Polymorphism of a single gene of CYP2E1, CYP1A1, GSTM1, EPHX1 might be not associated with the susceptibility of PHC, but when they combined with each other or combined with smoking or drinking; the risks of PHC were increased. These results suggest that gene-gene or gene-external exposure factors interaction play an importance role in the susceptibility of PHC, in addition, it necessary to take targeted preventive measures for PHC in Guangxi Province.
引文
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[2]张春燕,黄天壬,余家华. 21世纪初广西肝癌的流行特征(英文)[J].癌症,2010(5):545-550.
[3] Reed J R, Eyer M, Backes W L. Functional interactions between cytochromes P450 1A2 and 2B4 require both enzymes to reside in the same phospholipid vesicle: evidence for physical complex formation[J]. J Biol Chem,2010,285(12):8942-8952.
[4] Walker K, Ginsberg G, Hattis D, et al. Genetic polymorphism in N-Acetyltransferase(NAT): Population distribution of NAT1 and NAT2 activity[J].J Toxicol Environ Health B CritRev,2009,12(5-6): 440-472.
[5] Malik M A, Upadhyay R, Modi D R, et al. Association of NAT2 gene polymorphisms with susceptibility to esophageal and gastric cancers in the Kashmir Valley[J]. Arch Med Res,2009,40(5):416-423.
[6] Chang T K, Chen J, Yang G, et al. Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin[J]. J Pineal Res,2010,48(1):55-64.
[7]邓伟.广西肝癌高发区谷胱苷肽转硫酶基因多态性与肝癌家族聚集性关系的研究[D].广西医科大学,2006.
[8]盛鹰.广西壮族人群肝癌家族聚集与细胞色素P450 2E1基因多态性等因素关系的研究[D].广西医科大学,2007.
[9]刘茶珍,边建超,沈福民,等.细胞色素P450 2E1基因多态与肝癌遗传易感性研究[J].癌症,2000(10):862-864.
[10] Yu S Z, Huang X E, Koide T, et al. Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinomain Haimen, China.[J]. Jpn J Cancer Res,2002,93(12):1287-1292.
[11]姜爱仁,吴建中,丁建华,等. CYP2E1基因多态性与肝癌易感性的关系[J].肿瘤防治杂志,2004(5):464-466.
[12] Wu M T, Lee J M, Wu D C, et al. Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan[J]. Br J Cancer,2002,87(5):529-532.
[13] Baxter S W, Choong D Y, Campbell I G. Microsomal epoxide hydrolase polymorphism and susceptibility to ovarian cancer[J]. Cancer Lett,2002,177(1):75-81.
[14]李照海,覃红,张洪.遗传学中的统计方法[M].北京:科学出版社, 2006: 4-11.
[15]王培桦,沈洪兵,陈峰,等.叉生分析在基因-环境交互作用研究中的应用与意义[J].中华流行病学杂志,2005(1).
[16] Watanabe J, Horiguchi S, Karibe A, et al. Effects of ryanodine on development of myogenic response in rat small skeletal muscle arteries[J]. Cardiovasc Res,1994,28(4):480-484.
[17] Seaton M J, Follansbee M H, Bond J A. Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes[J]. Carcinogenesis, 1995, 16(10):2287-2293.
[18]周信娟,黄天壬.中国人群细胞色素CYP2E1基因多态性与肝癌易感性的Meta分析[J].中国癌症防治杂志,2010(4):273-275.
[19] Jaiswal A K, Gonzalez F J, Nebert D W. Human dioxin-inducible cytochrome P1-450: complementary DNA and amino acid sequence[J]. Science,1985,228(4695):80-83.
[20] Nebert D W, Mckinnon R A, Puga A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer[J]. DNA CellBiol,1996,15(4):273-280.
[21]郑志祥. CYP1A1基因多态性与原发性肝癌发生的相关性研究[D].广西医科大学,2007.
[22]吴秀华,杨晓燕,段炜,等.细胞色素p450基因多态性与肝癌遗传易感性的关系[J].武警医学院学报,2007(1):47-48.
[23] Fretland A J, Omiecinski C J. Epoxide hydrolases: biochemistry and molecular biology[J]. Chem Biol Interact,2000,129(1-2):41-59.
[24]贺菽嘉,顾永耀,林文珍,等. EPHX 1基因多态性与原发性肝癌易感性的关系[J].肿瘤,2008(2):125-128.
[25] Hassett C, Robinson K B, Beck N B, et al. The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization[J]. Genomics,1994,23(2):433-442.
[26]刘自光.解毒酶基因GSTT_1、EPHX多态性与肝癌的相关性[D].广西医科大学,2003.
[27] Bataller R, North K E, Brenner D A.Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal[J].Hepatology,2003,37(3): 493-503.
[28]缪文彬,王威,冀芳,等.中国人群GSTM1基因多态与原发性肝癌关系的Meta分析[J].环境与职业医学,2008(4).
[29]朱文昌,陈清,罗晨玲,等. CYP1A1与GSTM1的多态性与原发性肝癌遗传易感性的关系研究[J].肿瘤防治杂志,2001(6):572-574.
[30]黄雪.代谢酶基因CYP1A1、GSTM1多态性和广西地区胃癌遗传易感性的病例对照研究[D].广西医科大学,2007.
[31]刘茶珍,边建超,江峰,等.药物代谢酶基因多态与肝癌关系研究[J].江西医学院学报,2003(2):30-32.
[32]裴广军,付莉,崔亚玲,等.中国人群饮酒与原发性肝癌关系的Meta分析[J].现代预防医学,2008(14):2626-2627.
[33] Nagy L E. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury[J]. Annu Rev Nutr,2004,24:55-78.
[34] Cederbaum A I. CYP2E1--biochemical and toxicological aspects and role in alcohol-induced liver injury[J]. Mt Sinai J Med,2006,73(4):657-672.
[35] Nagy L E. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury[J]. Annu Rev Nutr,2004,24:55-78.
[36]叶新平,彭涛,刘唐威,等. ALDH2和CYP2E1基因多态性及饮酒习惯与肝细胞癌易感性的关系[J].卫生研究,2010(1).
[37]郭惠媛,边建超,江峰,等.洛阳市GSTM1和GSTT1缺失基因型与肝癌的遗传易感性[J].肿瘤,2005(1):58-61.
[38]贺菽嘉,顾永耀,廖志红. GSTM1基因多态性和烟酒习惯与原发性肝癌易感性的关系[J].广西医科大学学报,2008(4).
[39]么鸿雁,陈辉,吕美霞,等.行为生活方式对恶性肿瘤发病影响的综合分析[J].中国公共卫生,2003(4).
[40] Batty G D, Kivimaki M, Gray L, et al. Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study[J]. Ann Oncol,2008,19(5):996-1002.
[41] Ohishi W, Fujiwara S, Cologne J B, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case- control study[J].Cancer Epidemiol Biomarkers Prev,2008,17(4): 846-854.
[42]张薇,高玉堂,王学励,等.吸烟与原发性肝癌关系的巢式病例对照研究[J].中华肿瘤杂志,2009,31(1):20-23.
[43]曹燕燕,边建超,江峰,等.环氧化物水解酶基因多态与肝癌的遗传易感性[J].复旦学报(医学版),2004(4):363-367.
[44]杨绍基.传染病学[M].北京:人民卫生出版社, 2002: 22-41.
[45]陈园生,王晓军,梁晓峰,等.中国东中西部地区乙型病毒性肝炎流行现状[J].中国计划免疫,2006(4).
[1] Reed J R, Eyer M, Backes W L. Functional interactions between cytochromes P450 1A2 and 2B4 require both enzymes to reside in the same phospholipid vesicle: evidence for physical complex formation[J]. J Biol Chem,2010,285(12):8942-8952.
[2] Walker K, Ginsberg G, Hattis D, et al. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity[J]. J Toxicol Environ Health B Crit Rev,2009,12(5-6):440-472.
[3] Malik M A, Upadhyay R, Modi D R, et al. Association of NAT2 gene polymorphisms with susceptibility to esophageal and gastric cancers in the Kashmir Valley[J]. Arch Med Res,2009,40(5):416-423.
[4] Chang T K, Chen J, Yang G, et al. Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin[J]. J Pineal Res,2010,48(1):55-64.
[5] Jaiswal A K, Gonzalez F J, Nebert D W. Human dioxin-inducible cytochrome P1-450: complementary DNA and amino acid sequence[J]. Science,1985,228(4695):80-83.
[6] Nebert D W, Mckinnon R A, Puga A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer[J]. DNA Cell Biol,1996,15(4):273-280.
[7]吴秀华,杨晓燕,段炜,等.细胞色素p450基因多态性与肝癌遗传易感性的关系[J].武警医学院学报,2007,16(1):47-48, 62页.
[8]刘茶珍,边建超,江峰,等.药物代谢酶基因多态与肝癌关系研究[J].江西医学院学报,2003(2):30-32.
[9] Mochizuki J, Murakami S, Sanjo A, et al. Genetic polymorphisms of cytochrome P450 in patients with hepatitis C virus-associated hepatocellular63carcinoma[J]. J Gastroenterol Hepatol,2005,20(8):1191-1197.
[10] Neafsey P, Ginsberg G, Hattis D, et al. Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): Population distribution of CYP2D6 activity[J]. J Toxicol Environ Health B Crit Rev,2009,12(5-6):334-361.
[11] Watanabe J, Horiguchi S, Karibe A, et al. Effects of ryanodine on development of myogenic response in rat small skeletal muscle arteries[J]. Cardiovasc Res,1994,28(4):480-484.
[12] Seaton M J, Follansbee M H, Bond J A. Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes[J]. Carcinogenesis, 1995, 16(10):2287-2293.
[13]周信娟,黄天壬.中国人群细胞色素CYP2E1基因多态性与肝癌易感性的Meta分析[J].中国癌症防治杂志,2010(4):273-275.
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[17] Wojnowski L. Genetics of the variable expression of CYP3A in humans[J]. Ther Drug Monit,2004,26(2):192-199.
[18] Bataller R, North K E, Brenner D A. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal[J]. Hepatology,2003,37(3): 493-503.
[19]缪文彬,王威,冀芳,等.中国人群GSTM1基因多态与原发性肝癌关系的Meta分析[J].环境与职业医学,2008(4).
[20] White D L, Li D, Nurgalieva Z, et al. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis.[J]. Am J Epidemiol,2008,167(4):377-389.
[21] Fretland A J, Omiecinski C J. Epoxide hydrolases: biochemistry and molecular biology[J]. Chem Biol Interact,2000,129(1-2):41-59.
[22]贺菽嘉,顾永耀,林文珍,等. EPHX 1基因多态性与原发性肝癌易感性的关系[J].肿瘤,2008(2):125-128.
[23]刘自光.解毒酶基因GSTT_1、EPHX多态性与肝癌的相关性[D].广西医科大学,2003.
[24] Kiran M, Chawla Y K, Kaur J. Glutathione-S-transferase and microsomal epoxide hydrolase polymorphism and viral-related hepatocellular carcinoma risk in India[J]. DNA Cell Biol,2008,27(12):687-694.
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[26]张秀峰,张小燕,边建超,等. NAT1基因多态性与肝癌的遗传易感性[J].中国癌症杂志,2004(3).
[27]高建平,黄跃东,朱青川,等. N-乙酰基转移酶基因多态性与肝癌易感性的关系[J].中华肝脏病杂志,2003(1).
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[29] Gelatti U, Covolo L, Talamini R, et al. N-Acetyltransferase-2, glutathione S-transferase M1 and T1 genetic polymorphisms, cigarette smoking and hepatocellular carcinoma: a case-control study[J]. Int J Cancer, 2005, 115(2): 301-306.
[2]张春燕,黄天壬,余家华. 21世纪初广西肝癌的流行特征(英文)[J].癌症,2010(5):545-550.
[3] Reed J R, Eyer M, Backes W L. Functional interactions between cytochromes P450 1A2 and 2B4 require both enzymes to reside in the same phospholipid vesicle: evidence for physical complex formation[J]. J Biol Chem,2010,285(12):8942-8952.
[4] Walker K, Ginsberg G, Hattis D, et al. Genetic polymorphism in N-Acetyltransferase(NAT): Population distribution of NAT1 and NAT2 activity[J].J Toxicol Environ Health B CritRev,2009,12(5-6): 440-472.
[5] Malik M A, Upadhyay R, Modi D R, et al. Association of NAT2 gene polymorphisms with susceptibility to esophageal and gastric cancers in the Kashmir Valley[J]. Arch Med Res,2009,40(5):416-423.
[6] Chang T K, Chen J, Yang G, et al. Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin[J]. J Pineal Res,2010,48(1):55-64.
[7]邓伟.广西肝癌高发区谷胱苷肽转硫酶基因多态性与肝癌家族聚集性关系的研究[D].广西医科大学,2006.
[8]盛鹰.广西壮族人群肝癌家族聚集与细胞色素P450 2E1基因多态性等因素关系的研究[D].广西医科大学,2007.
[9]刘茶珍,边建超,沈福民,等.细胞色素P450 2E1基因多态与肝癌遗传易感性研究[J].癌症,2000(10):862-864.
[10] Yu S Z, Huang X E, Koide T, et al. Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinomain Haimen, China.[J]. Jpn J Cancer Res,2002,93(12):1287-1292.
[11]姜爱仁,吴建中,丁建华,等. CYP2E1基因多态性与肝癌易感性的关系[J].肿瘤防治杂志,2004(5):464-466.
[12] Wu M T, Lee J M, Wu D C, et al. Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan[J]. Br J Cancer,2002,87(5):529-532.
[13] Baxter S W, Choong D Y, Campbell I G. Microsomal epoxide hydrolase polymorphism and susceptibility to ovarian cancer[J]. Cancer Lett,2002,177(1):75-81.
[14]李照海,覃红,张洪.遗传学中的统计方法[M].北京:科学出版社, 2006: 4-11.
[15]王培桦,沈洪兵,陈峰,等.叉生分析在基因-环境交互作用研究中的应用与意义[J].中华流行病学杂志,2005(1).
[16] Watanabe J, Horiguchi S, Karibe A, et al. Effects of ryanodine on development of myogenic response in rat small skeletal muscle arteries[J]. Cardiovasc Res,1994,28(4):480-484.
[17] Seaton M J, Follansbee M H, Bond J A. Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes[J]. Carcinogenesis, 1995, 16(10):2287-2293.
[18]周信娟,黄天壬.中国人群细胞色素CYP2E1基因多态性与肝癌易感性的Meta分析[J].中国癌症防治杂志,2010(4):273-275.
[19] Jaiswal A K, Gonzalez F J, Nebert D W. Human dioxin-inducible cytochrome P1-450: complementary DNA and amino acid sequence[J]. Science,1985,228(4695):80-83.
[20] Nebert D W, Mckinnon R A, Puga A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer[J]. DNA CellBiol,1996,15(4):273-280.
[21]郑志祥. CYP1A1基因多态性与原发性肝癌发生的相关性研究[D].广西医科大学,2007.
[22]吴秀华,杨晓燕,段炜,等.细胞色素p450基因多态性与肝癌遗传易感性的关系[J].武警医学院学报,2007(1):47-48.
[23] Fretland A J, Omiecinski C J. Epoxide hydrolases: biochemistry and molecular biology[J]. Chem Biol Interact,2000,129(1-2):41-59.
[24]贺菽嘉,顾永耀,林文珍,等. EPHX 1基因多态性与原发性肝癌易感性的关系[J].肿瘤,2008(2):125-128.
[25] Hassett C, Robinson K B, Beck N B, et al. The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization[J]. Genomics,1994,23(2):433-442.
[26]刘自光.解毒酶基因GSTT_1、EPHX多态性与肝癌的相关性[D].广西医科大学,2003.
[27] Bataller R, North K E, Brenner D A.Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal[J].Hepatology,2003,37(3): 493-503.
[28]缪文彬,王威,冀芳,等.中国人群GSTM1基因多态与原发性肝癌关系的Meta分析[J].环境与职业医学,2008(4).
[29]朱文昌,陈清,罗晨玲,等. CYP1A1与GSTM1的多态性与原发性肝癌遗传易感性的关系研究[J].肿瘤防治杂志,2001(6):572-574.
[30]黄雪.代谢酶基因CYP1A1、GSTM1多态性和广西地区胃癌遗传易感性的病例对照研究[D].广西医科大学,2007.
[31]刘茶珍,边建超,江峰,等.药物代谢酶基因多态与肝癌关系研究[J].江西医学院学报,2003(2):30-32.
[32]裴广军,付莉,崔亚玲,等.中国人群饮酒与原发性肝癌关系的Meta分析[J].现代预防医学,2008(14):2626-2627.
[33] Nagy L E. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury[J]. Annu Rev Nutr,2004,24:55-78.
[34] Cederbaum A I. CYP2E1--biochemical and toxicological aspects and role in alcohol-induced liver injury[J]. Mt Sinai J Med,2006,73(4):657-672.
[35] Nagy L E. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury[J]. Annu Rev Nutr,2004,24:55-78.
[36]叶新平,彭涛,刘唐威,等. ALDH2和CYP2E1基因多态性及饮酒习惯与肝细胞癌易感性的关系[J].卫生研究,2010(1).
[37]郭惠媛,边建超,江峰,等.洛阳市GSTM1和GSTT1缺失基因型与肝癌的遗传易感性[J].肿瘤,2005(1):58-61.
[38]贺菽嘉,顾永耀,廖志红. GSTM1基因多态性和烟酒习惯与原发性肝癌易感性的关系[J].广西医科大学学报,2008(4).
[39]么鸿雁,陈辉,吕美霞,等.行为生活方式对恶性肿瘤发病影响的综合分析[J].中国公共卫生,2003(4).
[40] Batty G D, Kivimaki M, Gray L, et al. Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study[J]. Ann Oncol,2008,19(5):996-1002.
[41] Ohishi W, Fujiwara S, Cologne J B, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case- control study[J].Cancer Epidemiol Biomarkers Prev,2008,17(4): 846-854.
[42]张薇,高玉堂,王学励,等.吸烟与原发性肝癌关系的巢式病例对照研究[J].中华肿瘤杂志,2009,31(1):20-23.
[43]曹燕燕,边建超,江峰,等.环氧化物水解酶基因多态与肝癌的遗传易感性[J].复旦学报(医学版),2004(4):363-367.
[44]杨绍基.传染病学[M].北京:人民卫生出版社, 2002: 22-41.
[45]陈园生,王晓军,梁晓峰,等.中国东中西部地区乙型病毒性肝炎流行现状[J].中国计划免疫,2006(4).
[1] Reed J R, Eyer M, Backes W L. Functional interactions between cytochromes P450 1A2 and 2B4 require both enzymes to reside in the same phospholipid vesicle: evidence for physical complex formation[J]. J Biol Chem,2010,285(12):8942-8952.
[2] Walker K, Ginsberg G, Hattis D, et al. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity[J]. J Toxicol Environ Health B Crit Rev,2009,12(5-6):440-472.
[3] Malik M A, Upadhyay R, Modi D R, et al. Association of NAT2 gene polymorphisms with susceptibility to esophageal and gastric cancers in the Kashmir Valley[J]. Arch Med Res,2009,40(5):416-423.
[4] Chang T K, Chen J, Yang G, et al. Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin[J]. J Pineal Res,2010,48(1):55-64.
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