非免疫相关基因多态性与乙肝后肝硬化易感性的研究
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摘要
背景与目的:乙肝病毒感染后有不同的临床转归,其中肝硬化危害最大。乙肝后肝硬化的发生不仅与环境因素和病毒因素有关,还与个体的遗传易感性密切相关。单核苷酸多态性(SNP)占人类可遗传变异的90%以上,是目前诠释疾病遗传易感性最好的遗传标记。细胞因子基因多态性与乙肝后肝硬化的关系已有较多的研究报道,但与肝硬化发生过程有关的一些非免疫基因多态性很少或没有报道,更缺乏较系统的研究。本项目将联合检测7个与肝硬化发生过程相关的非免疫基因多态性位点,探讨它们与乙肝后肝硬化遗传易感性的关系。
方法:(1)研究对象:乙肝后肝硬化168例(病例组)和无症状乙肝病毒携带者155例(对照组)。(2)基因多态性分析:酚-氯仿法提取外周血基因组DNA,采用限制性片段长度多态性(PCR-RFLP)方法分析各基因位点的基因型。(3)计算各位点的基因型和等位基因频率,采用卡方检验比较它们的组间差异,并进行Hardy-Weinberg平衡吻合度检验。(4)分别以总样本和性别分层样本进行单因素Logistic回归分析,计算各基因型及等位基因的比数比(OR)及95%可信区间,并进行多因素Logistic回归分析筛选独立的危险和保护基因型和等位基因。
结果:(1)血管紧张素原基因-20A/C多态位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但多因素分析显示与女性HBV感染者肝硬化风险可能有一定关系,AA基因型和C等位基因的OR接近有统计学意义(P=0.064、0.080)。(2)血管紧张素原基因-6A/G多态位点的基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但多因素分析显示男性HBV感染者AA是易感基因型(OR=1.927, P=0.047),G是保护性等位基因(OR=0.508, P=0.047)。(3)雌激素受体α基因-29T/C多态位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但单因素Logistic回归分析显示该位点与女性乙肝后肝硬化易感性关系密切,TC为易感基因型(OR=3.336, P=0.007),CC为保护基因型(OR=0.327, P=0.015),T为易感等位基因(OR=3.061, P=0.015),多因素分析仍显示TC是女性易感基因型(OR=3.454,P=0.027),T是易感等位基因(OR=3.554,P=0.024)。(4)基质金属蛋白酶9基因-1562C/T位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间都非常接近,无统计学意义(P>0.10),单因素和多因素分析也未显示其与肝硬化易感性有关。(5)微粒体环氧化物水解酶基因Tyr113His位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),单因素和多因素分析也未显示它们与乙肝后肝硬化易感性有关。(6)微粒体环氧化物水解酶基因-613C/T位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异也无统计学意义(P>0.10),但该位点与女性乙肝后肝硬化易感性可能有一定的关系,单因素分析显示TT基因型和C等位基因的OR接近有统计学意义(P=0.089)。(7)谷胱甘肽转硫酶M1有空白基因型和正常基因型两种,其各基因型频率在肝硬化组和HBsAg携带组之间都非常接近,无统计学意义(P>0.10),多因素分析也未显示其与乙肝后肝硬化相关。(8)多因素Logistic回归分析显示本研究所检测的7个基因多态性位点中,AGT-6AA是独立的男性乙肝后肝硬化易感基因型,G是独立的男性保护性等位基因,ESR1+29TC基因型和T等位基因都是独立的女性乙肝后肝硬化的危险因子。
结论:(1)血管紧张素原基因-20A/C和-6A/G位点多态性与乙肝后肝硬化易感性有一定关系,其中-6A/G位点与男性乙肝后肝硬化易感性相关,-20A/C位点与女性乙肝后肝硬化易感性有一定相关性。(2)ESR1基因+29T/C位点基因多态性与女性乙肝后肝硬化易感性密切相关,与男性无明显相关。(3)基质金属蛋白酶9基因-1562C/T位点与乙肝后肝硬化易感性无明显相关。(4)微粒体环氧化物水解酶基因-613C/T和Tyr113His两个多态位点均与乙肝后肝硬化易感性无明显相关。(5)GSTM1空白或正常基因型与乙肝后肝硬化易感性无明显相关。(6)AGT-6A/G位点是与男性乙肝后肝硬化易感性相关的独立因素,ESR1 +29T/C位点是与女性乙肝后肝硬化易感性相关的独立因素。
Background and Objective: There are different clinical outcomes in patients with hepatitis B virus infection, and the most serious condition is hepatic cirrhosis. The development of HBV-related hepatic cirrhosis is associated with not only environmental and viral factors but also hereditary susceptibility. Single nucleotide polymorphisms (SNPs), account for more than 90% of human genetic variations, are the best genetic markers to indicate genetic susceptibility of diseases. There are some studies reported on the relationships between cytokine gene polymorphisms and the HBV-related hepatic cirrhosis, but few studies on the non-immune-related gene polymorphisms associated with the development of HBV-related cirrhosis, and lack of systematic researches about them. In the present study, we detected 7 genetic polymorphism sites of non-immune-related genes possiblely associated with the development of liver cirrhosis, and analyzed the relationship between them and the susceptibility of HBV-related hepatic cirrhosis.
Methods: (1) Patients: 168 cirrhosis patients with HBV infection (case group) and 155 asymptomatic HBV carriers (control group) were recruited. (2) Gene polymorphism analysis: peripheral blood genomic DNA was extracted by phenol-chloroform method. Polymerase chain reaction-restriction fragment length polymorphism was used to determine the genotypes of each polymorphism sites. (3) Genotype and allele frequencies in each site were calculated and their differences between two groups were compared by chi-square test, and Hardy-Weinberg equilibriums of genotypes was verified by chi-square test. (4) The odds ratios (ORs) and their 95% confidence intervals of all genotypes and alleles were calculated by univariate Logistic regression analysis in total sample and gender-stratified sub-samples, respectively. Multivariate Logistic regression analysis was used to screen independent risk and protective genotypes and alleles.
Results: (1) The differences of all genotype and allele frequencies at AGT-20A/C site were not significant between case group and control group (P>0.10). However, multivariate analysis showed a probable association between this site and susceptibility of HBV-related cirrhosis in female patients, the ORs of genotype AA and allele C nearly significant (P=0.064, 0.080). (2) The differences of all genotype and allele frequencies at AGT -6A/G site were not significant between case group and control group (P>0.10), but multivariate analysis showed that AA was a risk genotype (OR=1.927, P=0.047) and G was protective allele (OR=0.508, P=0.047) in male patients. (3) The differences of all genotype and allele frequencies at ESR1 +29T/C site were not significant between case group and control group (P>0.10). However, univariate analysis showed that it is closely associated with susceptibility of female cirrhosis. The TC was susceptible genotype (OR=3.336, P=0.007), CC was a protective genotype (OR=0.327, P=0.015), and T was susceptible allele (OR=3.061, P=0.015) in female patients. Multivariate analysis confirmed that TC was susceptible genotype (OR=3.454,P=0.027) and T was susceptible allele (OR=3.554,P=0.024) in female. (4) The differences of all genotype and allele frequencies at MMP9 -1562C/T site were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show association between it and susceptibility of HBV-related cirrhosis. (5) The differences of all genotype and allele frequencies at MEH Tyr113His site were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show association between it and susceptibility of HBV-related cirrhosis. (6) The differences of all genotype and allele frequencies at MEH -613C/T site were not significant between case group and control group (P>0.10), but there seemed some correlation between this site and susceptibility of female HBV-related liver cirrhosis. In female patients, the ORs of TT genotype and C allele were nearly significant (P=0.089, 0.089). (7) The differences of GSTM1 genotype frequencies were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show that this site is associated with susceptibility of HBV-related liver cirrhosis. (8) Multivariate Logistic regression analysis showed that in the 7 genetic variations detected, AGT-6AA was an independent risk genotype and AGT-6G was an independent protective allele for HBV-related cirrhosis development in male patients, and both of ESR1+29TC genotype and T allele were risk factors for HBV-related cirrhosis development in female patients.
Conclusions: (1) AGT gene polymorphisms are associated with susceptibility of HBV-related liver cirrhosis, in which -6A/G site correlated with susceptibility of male cirrhosis, and -20A/C correlated with susceptibility of female cirrhosis. (2) There is significant association between gene polymorphisms at position +29T/C of ER1 and susceptibility of female HBV-related liver cirrhosis, but without significant association with male. (3) There is no significant association between gene polymorphisms at position -1562 of MMP-9 and susceptibility of HBV-related liver cirrhosis. (4) There is no significant association between gene polymorphisms at position -613C/T or -Tyr113His of MEH and susceptibility of HBV-related liver cirrhosis. (5) There is no significant association between null or normal genotype of GSTM1 and susceptibility of HBV-related liver. (6) AGT-6A/G site is an independent factor for male cirrhosis development and ESR1+29T/C site is an independent factor for female cirrhosis development.
方法:(1)研究对象:乙肝后肝硬化168例(病例组)和无症状乙肝病毒携带者155例(对照组)。(2)基因多态性分析:酚-氯仿法提取外周血基因组DNA,采用限制性片段长度多态性(PCR-RFLP)方法分析各基因位点的基因型。(3)计算各位点的基因型和等位基因频率,采用卡方检验比较它们的组间差异,并进行Hardy-Weinberg平衡吻合度检验。(4)分别以总样本和性别分层样本进行单因素Logistic回归分析,计算各基因型及等位基因的比数比(OR)及95%可信区间,并进行多因素Logistic回归分析筛选独立的危险和保护基因型和等位基因。
结果:(1)血管紧张素原基因-20A/C多态位点的各基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但多因素分析显示与女性HBV感染者肝硬化风险可能有一定关系,AA基因型和C等位基因的OR接近有统计学意义(P=0.064、0.080)。(2)血管紧张素原基因-6A/G多态位点的基因型及等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但多因素分析显示男性HBV感染者AA是易感基因型(OR=1.927, P=0.047),G是保护性等位基因(OR=0.508, P=0.047)。(3)雌激素受体α基因-29T/C多态位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),但单因素Logistic回归分析显示该位点与女性乙肝后肝硬化易感性关系密切,TC为易感基因型(OR=3.336, P=0.007),CC为保护基因型(OR=0.327, P=0.015),T为易感等位基因(OR=3.061, P=0.015),多因素分析仍显示TC是女性易感基因型(OR=3.454,P=0.027),T是易感等位基因(OR=3.554,P=0.024)。(4)基质金属蛋白酶9基因-1562C/T位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间都非常接近,无统计学意义(P>0.10),单因素和多因素分析也未显示其与肝硬化易感性有关。(5)微粒体环氧化物水解酶基因Tyr113His位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异无统计学意义(P>0.10),单因素和多因素分析也未显示它们与乙肝后肝硬化易感性有关。(6)微粒体环氧化物水解酶基因-613C/T位点的各基因型和等位基因频率在肝硬化组和HBsAg携带组之间差异也无统计学意义(P>0.10),但该位点与女性乙肝后肝硬化易感性可能有一定的关系,单因素分析显示TT基因型和C等位基因的OR接近有统计学意义(P=0.089)。(7)谷胱甘肽转硫酶M1有空白基因型和正常基因型两种,其各基因型频率在肝硬化组和HBsAg携带组之间都非常接近,无统计学意义(P>0.10),多因素分析也未显示其与乙肝后肝硬化相关。(8)多因素Logistic回归分析显示本研究所检测的7个基因多态性位点中,AGT-6AA是独立的男性乙肝后肝硬化易感基因型,G是独立的男性保护性等位基因,ESR1+29TC基因型和T等位基因都是独立的女性乙肝后肝硬化的危险因子。
结论:(1)血管紧张素原基因-20A/C和-6A/G位点多态性与乙肝后肝硬化易感性有一定关系,其中-6A/G位点与男性乙肝后肝硬化易感性相关,-20A/C位点与女性乙肝后肝硬化易感性有一定相关性。(2)ESR1基因+29T/C位点基因多态性与女性乙肝后肝硬化易感性密切相关,与男性无明显相关。(3)基质金属蛋白酶9基因-1562C/T位点与乙肝后肝硬化易感性无明显相关。(4)微粒体环氧化物水解酶基因-613C/T和Tyr113His两个多态位点均与乙肝后肝硬化易感性无明显相关。(5)GSTM1空白或正常基因型与乙肝后肝硬化易感性无明显相关。(6)AGT-6A/G位点是与男性乙肝后肝硬化易感性相关的独立因素,ESR1 +29T/C位点是与女性乙肝后肝硬化易感性相关的独立因素。
Background and Objective: There are different clinical outcomes in patients with hepatitis B virus infection, and the most serious condition is hepatic cirrhosis. The development of HBV-related hepatic cirrhosis is associated with not only environmental and viral factors but also hereditary susceptibility. Single nucleotide polymorphisms (SNPs), account for more than 90% of human genetic variations, are the best genetic markers to indicate genetic susceptibility of diseases. There are some studies reported on the relationships between cytokine gene polymorphisms and the HBV-related hepatic cirrhosis, but few studies on the non-immune-related gene polymorphisms associated with the development of HBV-related cirrhosis, and lack of systematic researches about them. In the present study, we detected 7 genetic polymorphism sites of non-immune-related genes possiblely associated with the development of liver cirrhosis, and analyzed the relationship between them and the susceptibility of HBV-related hepatic cirrhosis.
Methods: (1) Patients: 168 cirrhosis patients with HBV infection (case group) and 155 asymptomatic HBV carriers (control group) were recruited. (2) Gene polymorphism analysis: peripheral blood genomic DNA was extracted by phenol-chloroform method. Polymerase chain reaction-restriction fragment length polymorphism was used to determine the genotypes of each polymorphism sites. (3) Genotype and allele frequencies in each site were calculated and their differences between two groups were compared by chi-square test, and Hardy-Weinberg equilibriums of genotypes was verified by chi-square test. (4) The odds ratios (ORs) and their 95% confidence intervals of all genotypes and alleles were calculated by univariate Logistic regression analysis in total sample and gender-stratified sub-samples, respectively. Multivariate Logistic regression analysis was used to screen independent risk and protective genotypes and alleles.
Results: (1) The differences of all genotype and allele frequencies at AGT-20A/C site were not significant between case group and control group (P>0.10). However, multivariate analysis showed a probable association between this site and susceptibility of HBV-related cirrhosis in female patients, the ORs of genotype AA and allele C nearly significant (P=0.064, 0.080). (2) The differences of all genotype and allele frequencies at AGT -6A/G site were not significant between case group and control group (P>0.10), but multivariate analysis showed that AA was a risk genotype (OR=1.927, P=0.047) and G was protective allele (OR=0.508, P=0.047) in male patients. (3) The differences of all genotype and allele frequencies at ESR1 +29T/C site were not significant between case group and control group (P>0.10). However, univariate analysis showed that it is closely associated with susceptibility of female cirrhosis. The TC was susceptible genotype (OR=3.336, P=0.007), CC was a protective genotype (OR=0.327, P=0.015), and T was susceptible allele (OR=3.061, P=0.015) in female patients. Multivariate analysis confirmed that TC was susceptible genotype (OR=3.454,P=0.027) and T was susceptible allele (OR=3.554,P=0.024) in female. (4) The differences of all genotype and allele frequencies at MMP9 -1562C/T site were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show association between it and susceptibility of HBV-related cirrhosis. (5) The differences of all genotype and allele frequencies at MEH Tyr113His site were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show association between it and susceptibility of HBV-related cirrhosis. (6) The differences of all genotype and allele frequencies at MEH -613C/T site were not significant between case group and control group (P>0.10), but there seemed some correlation between this site and susceptibility of female HBV-related liver cirrhosis. In female patients, the ORs of TT genotype and C allele were nearly significant (P=0.089, 0.089). (7) The differences of GSTM1 genotype frequencies were not significant between case group and control group (P>0.10), and univariate and multivariate analyses did not show that this site is associated with susceptibility of HBV-related liver cirrhosis. (8) Multivariate Logistic regression analysis showed that in the 7 genetic variations detected, AGT-6AA was an independent risk genotype and AGT-6G was an independent protective allele for HBV-related cirrhosis development in male patients, and both of ESR1+29TC genotype and T allele were risk factors for HBV-related cirrhosis development in female patients.
Conclusions: (1) AGT gene polymorphisms are associated with susceptibility of HBV-related liver cirrhosis, in which -6A/G site correlated with susceptibility of male cirrhosis, and -20A/C correlated with susceptibility of female cirrhosis. (2) There is significant association between gene polymorphisms at position +29T/C of ER1 and susceptibility of female HBV-related liver cirrhosis, but without significant association with male. (3) There is no significant association between gene polymorphisms at position -1562 of MMP-9 and susceptibility of HBV-related liver cirrhosis. (4) There is no significant association between gene polymorphisms at position -613C/T or -Tyr113His of MEH and susceptibility of HBV-related liver cirrhosis. (5) There is no significant association between null or normal genotype of GSTM1 and susceptibility of HBV-related liver. (6) AGT-6A/G site is an independent factor for male cirrhosis development and ESR1+29T/C site is an independent factor for female cirrhosis development.
引文
1. World Health Organization. Hepatitis B[OB/OL].[2007- 4-26]. http://who.int/mediacentre/factsheets/fs204/en/index.htm1.
2.张焜和主编.乙肝病毒感染的基础与临床.江西科技出版社1999.
3.于淑丽,龚幼龙,邵瑞太,等.慢性乙肝、乙肝后肝硬化和肝癌的疾病负担.中国公共卫生, 2003,19 (3):280-282.
4.李洪权,李卓,张作文,等.乙型肝炎病毒基因型在无症状感染者、慢性乙肝和肝硬化患者中分布研究.中国预防医学, 2005, 6( 2):213-215.
5. Gressner AM, Schuppan D, Bircher J, et a1. Oxford Textbook of Clinical Hepatology. Oxford: Oxford Medi-cal Publications, 1999: 607-627.
6. He YL, Zhao YR, Zhang SL, et al. Host susceptibility to persistent hepatitis B virus infection. World J Gastroenterol, 2006, 12(30): 4788-4793.
7.林菊生,程元桥,田德英,等. HLA2 DRB1和肿瘤坏死因子α基因多态性与肝硬化的遗传易感性.中华内科杂志, 2002, 41(12):818-821.
8. Xiao F, Wei H, Song S, et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol, 2006, 21(9):1488-1491.
9. Romero-Gomez M, Montes-Cano MA, Otero-Fernandez MA, et al. SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C. Gut, 2004, 53(3):446-450.
10. Burim RV, Canalle R, Martinelli Ade L, et al. Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics. Mutagenesis, 2004,19(4):291-298.
11. Chevillard C, Moukoko CE, Elwali NE, et al. IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). J Immunol, 2003, 171(10):5596-5601.
12. Donaldson P, Agarwal K, Craggs A, et al. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut, 2001, 48(3):397-402
13. The International HapMap Consortium. The international HapMap project. Nature, 2003, 426(6968): 789-796
14. Engle LJ, Simpson CL, Landers JE. Using high-throughput SNP technologies to study cancer. Oncogene, 2006, 25(11):1594-1601.
15. Bataller R, North KE, Brenner DA. Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal. Hepatology, 2003, 37:493-503.
16. Richardson MM, Powell EE, Barrie HD, et al. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet, 2005, 42(7):e45.
17. Wang LD, Zheng S, Liu B, et al. CYP1A1, GSTs and mEH polymorphisms and susceptibility to esophageal carcinoma: Study of population from a high- incidence area in north China. World J Gastroenterol, 2003,9(7):1394-1397.
18. Deng G, Zhou GQ, Zhai Y, et al.Association of estrogen receptorαpolymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology, 2004, 40(2):318-326.
19. Sonzogni L, Silvestri L, De Silvestri A, et al. Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease. Hepatology, 2002, 36(1):195-201.
20.梁群,刘群,李长春,等.基质金属蛋白酶- 9基因多态性与乙型肝炎肝硬化的关系.实用肝脏病杂志, 2007, 10(4):229-231.
21. Xiao F, Wei HS, Song SJ, et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. Hepatology, 2006, 21:1488-1491.
22. Yoshiji H, Kuriyama S, Yoshii J, et a1. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology, 2001, 34:745-750.
23. Paizis G, Gilbert RE, Cooper ME, et a1. Effects of angiotensin IItype 1 receptor blockade on experimental hepatic fibrogenesis.J Hepatol 2001;35:376—385.
24.李乾,张桂英,李新华.血管紧张素Ⅱ与肝纤维化. World Chin J Digestol, 2003, 11(3):334-337.
25.李立新,王宇,张忠涛,等.血管紧张素Ⅱ受体拮抗剂抗纤维化及对Ⅱ型胶原基因表达影响的实验研究.中华肝胆外科杂志, 2004, 1:55-56.
26. Powell EE, Edwards-Smith CJ, Hay JL. et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology, 2000, 31(4):828-33.
27.肖凡,魏红山,董庆鸣,等.血管紧张素原基因5′端核心启动子区(-6)A～G变异与肝硬化相关性.中华肝脏病杂志, 2006 , l4(8):609-610.
28. Forresl EH, Thorburn D, Spence E, et al. Polymorphism of angiotensin system and the severity of fibrosis in chronic hepatitis Cvirus infection. J Viral Hepat, 2005, l2:519-524.
29. Yasuda M, Shimizu I, Shiba M, et al. Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rat. Hepatology, 1999, 29(3):719-727
30. Shimizu I, Mizobuchi Y, Yasuda M, et al. Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut, 1999, 44(2):127-136
31. Smith E P, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med, 1994, 331(16):1056-1061
32. Almog Y, Klein A, Adler R, et al. Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected Hep G-2 cells. Antiviral Res, 1992, 19:285-293
33. Tur-Kaspa R, Shaul Y, Moore DD, et al. The glucocorticoid receptor recognize a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology, 1988, 167:630-633.
34. Deng G, Zhou G, Zhai Y, et al. Association of estrogen receptor a polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology, 2004, 40:318-326.
35. Shearman AM, Cupples LA, Demissie S, et al. Association between estrogen receptor alpha gene variation and cardiovascular disease [J]. JAMA, 2003, 290(17):2263-2270.
36. Kitawaki J, Obayashi H, Ishihara H, et al. Oestrogen receptoralpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata [J]. Hum Reprod, 2001, 16(1):51-55.
37. Kobayashi S, Inoue S, Hosoi T, et al. Association of bone mineral density with polymorphism of the estrogen receptor gene [J]. J Bone Miner Res, 1996, 11(3):306-311.
38. Xie JP, Gong XQ, Tan DM, et al. Estrogen receptor gene polymorphisms and HBV-induced liver cirrhosis. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006, 31(3):379-82.
39. Zhang B, YE S, Herrmann SM, et a1. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosc1erosis [J]. Circulation, 1999, 99(14):1788-94.
40.刘加强,杨富生.关于基质金属蛋白酶9的最新进展[J].牙体牙髓牙周病学杂志, 2005, 15(3):12-15.
41.谢彦华,李里,王立娥,等.基质金属蛋白酶-2,-9与肝纤维化[J].临床肝胆病杂志, 2002, 18(2):82-83.
42.金博,荣佳,岳欣,等.基质金属蛋白酶-2 -9及金属蛋白酶组织抑制物-1基因在病变肝脏的表达[J].海军总医院学报, 2006, 19(4):205-208.
43. Ghilardi G, Biondi ML, MeMonti M, et al. Matrix metalloproteinase-1 and Matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke, 2002, 33:2408-12.
44. Zhang B, Dhillon S, Geary I, et al. Polymorphisms in matrix metalloproteinase-1,-3,-9,and -12 genes in relation to subarachnodi hemorrhage.Stroke 2001;32:2198-202.
45. Ghilardi G, Biondi ML, Caputo M et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility. Clin. Cancer Res , 2002, 8:3820-3.
46. Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase(MMP)-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102:526-9.
47. Okamoto K, Mimura K, Murawaki Y, et al. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease. J Gastroenterol Hepatol, 2005, 20(7):1102-8.
48. Guengerich FP. Epoxide hydrolase, properties and metabolic roles. Rev Biochem Toxicol, 1982, 4:5-30.
49. Hassett C, Lin J, Carty CL, et al. Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression. Arch Biochem Biophys, 1997, 337:275-283.
50. Laurenzana EM, Hassett C, Omiecinski CJ. Post-transcriptional regulation of human microsomal epoxide hydrolase. Pharmacogenetics, 1998, 8:157-167.
51. Strickler SM, Dansky LV, Miller MA, et al. Genetic predisposition to phenytoin-induced birth defects. Lancet, 1985, 2:746-749.
52. Sandford AJ, Chagani T, Weir TD, et al. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med, 2000, 163:469-473.
53. Benhamou S, Reinikainen M, Bouchardy C, et al. Association between lung cancer and microsomal epoxide hydrolase genotypes.Cancer Res, 1998, 58:5291-5293.
54. McGlynn KA, Rosvold EA, Lustbader ED, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.Proc Natl Acad Sci USA , 1995, 92:2384-2387.
55. Wong NA, Rae F, Bathgate A, et al. Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. Toxicol Lett, 2000, 115(1):17-22.
56. Truelove AL, Oleksyk TK, Shrestha S, et al. Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome. Int J Immunogenet, 2008, 35(3):255-64.
57. Yang Y, Cheng JZ, Singhal SS, et al. Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem, 2001, 276(22):19220-19230.
58. Rao AV, Shaha C. Role of glutathione s-transferases in oxidative stress-induced male germ cell apoptosis. Free Radical Biol Med, 2000, 29:1015-1027.
59. Whalen R, Boyer TD. Human glutathione S-transferases. Semin Liver Dis, 1998, 18: 345-358.
60. Frenzer A, Butler WJ, Norton ID, et al. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol, 2002, 17:177-182.
61. Rodrigo L, Alvarez V, Rodriguez M, et al. N-acetyltransferase-2, glutathione s-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study. Scand J Gastroenterol, 1999, 34:303-307.
62. Chen SY, Wang LY, Lunn RM, et al. Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls. Int J Cancer, 2002, 99(1):14-21.
63. Zhong S, Tang MW, Yeo W, et al. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res, 2002, 8(4): 1087-1092.
64. Ghobadloo SM, Yaghmaei B, Bakayev V, et al. GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis.J Gastrointest Surg, 2004, 8(4):423-7.
65. Ghobadloo SM, Yaghmaei B, Allameh A, et al. Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers. Clin Biochem, 2006, 39(1):46-9.
1. World Health Organization.Hepatitis B[OB/OL].[2007—4—26].http://who.int/mediacentre/factsheets/fs204/en/index.htm1.
2. Lee WM.Hepatitis B virus infection.N Engl J Med 1997;337:1733-1745.
3.张焜和主编.乙肝病毒感染的基础与临床.江西科技出版社1999.
4.于淑丽,龚幼龙,邵瑞太等.慢性乙肝、乙肝后肝硬化和肝癌的疾病负担.中国公共卫生2003,19 (3):280-282.
5.李洪权,李卓,张作文,等.乙型肝炎病毒基因型在无症状感染者、慢性乙肝和肝硬化患者中分布研究[J].中国预防医学2005;6:213—215.
6. Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. World J Gastroenterol 2003;9 :641–644.
7. Wasmuth HE, Lammert F, Matern S. Genetic risk faction for hepatic fibrosis in chronic liver diseases. Med Klin (Munich) 2003;98(12):754-762.
8. Gressner AM, Schuppan D, Bircher J,Benhamou JP,et a1.Oxford Textbook of Clinical Hepatology.Oxford:Oxford Medi-cal Publications 1999:607-627.
9. Yang Y ,Cheng JZ,Singhal SS, Saini M, Pandya U, Awasthi S, Awasthi YC. Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem 2001; 276(22):19220-19230.
10. Rao AV,Shaha C. Role of glutathione s-transferases in oxidative stress-induced male germ cell apoptosis. Free Radical Biol Med 2000 ;29:1015–1027.
11. Whalen R ,Boyer TD. Human glutathione S-transferases. Semin Liver Dis 1998;18 : 345–358.
12. Cabre M, Camps J, Paternain JL, Ferre N, Joven J. Time course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. Hepatology 1999 ;29 :664–669.
13. Frenzer A, Butler WJ, Norton ID, Wilson JS, Apte MV, Pirola RC,et al. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol 2002;17:177–182.
14. Rodrigo L, Alvarez V, Rodriguez M, Perez R, Alvarez R,Coto E. N-acetyltransferase-2, glutathione s-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study. Scand J Gastroenterol 1999; 34 :303–307.
15. Chen SY, Wang LY, Lunn RM, Tsai WY, Lee PH, Lee CS, et al. Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls. Int J Cancer 2002 May 1;99(1):14–21.
16. Zhong S,Tang MW, Yeo W,Liu C, Lo YM, Johnson PJ. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res. 2002 Apr;8 (4): 1087–1092.
17. Ghobadloo SM, Yaghmaei B, Bakayev V,et al.GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis.J Gastrointest Surg 2004 May-Jun;8(4):423-7.
18. Ghobadloo SM, Yaghmaei B, Allameh A, et al. Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers. Clin Biochem 2006 Jan;39(1):46-9.
19. Guengerich FP. Epoxide hydrolase,properties and metabolic roles. Rev Biochem Toxicol 1982;4:5-30.
20. Omiecinski CJ,Aicher L,Holubkov R,Checkoway H. Human peripheral lymphocytes as indicators of microsomal epoxide hydrolase activity in liver and lung Pharmacogenetics 1993;3:150-158.
21. Hassett C,Lin J.Carty CL,Laurenzana EM,Omiecinski CJ.Human hepatic microsomal epoxide hydrolase:comparative analysis of polymorphic expression.Arch Biochem Biophys 1997;337:275-283.
22. Hassett C,Aicher L,Sidhu JS,Omiecinski CJ.Human microsomal epoxide hydrolase;genetic polymorphism and functional expression in vitro of amino acid variants.Hum Mol Genet 1994;3:412-428.
23. Omiecinski CJ,Hassett C,Hosagrahara V.Epoxide hydrolase-polymorphism and role in toxicology.Toxicol Lett 2000;112:365-370.
24. Laurenzana EM,Hassett C,Omiecinski CJ.Post-transcriptional regulation of human microsomal epoxide hydrolase.Pharmacogenetics 1998;8:157-167.
25. Strickler SM,Dansky LV,Miller MA,Seni MH,Andermann E,Spielberg SP.Genetic predisposition to phenytoin-induced birth defects.Lancet 1985;2:746-749.
26. Smith CAD,Harrison DJ.Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema.Lancet 1997;350:630-633.
27. Sandford AJ,Chagani T,Weir TD,Connett JE,Anthonisen NR,Pare PD.Susceptibility genes for rapid decline of lung function in the lung health study.Am J Respir Crit Care Med 2000;163:469-473.
28. Benhamou S,Reinikainen M,Bouchardy C,Dayer P,Hirvonen A.Association between lung cancer and microsomal epoxide hydrolase genotypes.Cancer Res 1998;58:5291-5293.
29. Gaedigk A,Spielberg SP,Grant DM.Characterization of the microsomal epoxide hydrolase in patients with anticonvulsant adverse drug reactions.Pharmacogenetics 1994;4:142-153.
30. McGlynn KA,Rosvold EA,Lustbader ED,Hu Y,Clapper ML,Zhou T,Wild CP,et al.Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.Proc Natl Acad Sci U S A 1995;92:2384-2387.
31. Raaka S,Hassett C,Omiecinski CJ. Human microsomal epoxide hydrolase:5′-flankingregion genetic polymorphisms. Carcinogenesis 1998;19:387-393.
32. Wong NA, Rae F, Bathgate A,et al. Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. Toxicol Lett 2000 Apr 10;115(1):17-22
33. Sonzogni L, Silvestri L, Silvestri AD, et al.Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease. Hepatology 2002 Jul;36(1):195-201
34. Yasuda M,Shimizu I,Shiba M,et al.Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rat. Hepatology 1999;29(3):719-727
35. Shimizu I,Mizobuchi Y,Yasuda M,et al.Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut 1999;44(2):127-136.
36. SmithE P,Boyd J,Frank GR,Takahashi H,Cohen RM,SpeckerB, William s TC,Lubahn DB,Korach KS. Estrogen resistance caused by a mutation in the estrogen—receptor gene in a man.N Engl J Med 1994;331(16):1056—1061
37. Shearman AM,Cupples LA,Demissie S,et al .Association between estrogen receptor alpha gene variation and cardiovascular disease[J].JAMA.2003,290(17):2263-2270.
38. Kitawaki J,Obayashi H,Ishihara H,et al.Oestrogen receptoralpha gene polymorphism is associated with endometriosis,adenomyosis and leiomyomata [J].Hum Reprod 2001;16(1):51-55.
39. Kobayashi S,Inoue S,Hosoi T,er al. Association of bone mineral density with polymorphism of the estrogen receptor gene [J].J Bone Miner Res 1996;11(3):306-311.
40. Almog Y.Klein A,Adler R,Laub O,Tur—Kaspa R.Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected Hep G-2 cells.Antiviral Res 1992;19:285—293
41. Tur-Kaspa R,Shaul Y,Moore DD,Burk RD,Okret S,Poellinger L,Shafritz DA.The glucocorticoid receptor recognize a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer.Virology 1988;167:630-633.
42. Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F. Association of estrogen receptor a polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004;40:318-326.
43. Xie JP, Gong XQ, Tan DM, Liu F, Zhou JL.Estrogen receptor gene polymorphisms and HBV-induced liver cirrhosis.Zhong Nan Da Xue Xue Bao Yi Xue Ban 2006 Jun;31(3):379-82.
44. Nagase H,Woessner JF,Matrix metalloproteinases.J Biol Chem 1999;274:21491-4.
45.谢彦华,李里,王立娥,等.基质金属蛋白酶-2-9及金属蛋白酶与肝纤维化[J].临床肝胆病杂志2002;18(2):82-83.
46. Iredak W,Benyon R C,Rctering J,et al.Mechanisms of spontaneous resolution of rat liver fibrosis,hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibition[J].J Clin Invest 1998;102(8):538-549.
47.王爱民,王宝恩,杨跃伟,等.慢性肝病金属蛋白酶组织抑制因子-1基因表达的研究.Chin J Dig 1999; 19:59-60.
48. Ye S,Watts GF,Mandalia S et al.Preliminary report:genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis.Brit.Heart J 1995;73:209-15.
49. Ghilardi G,Biondi ML,MeMonti M et al.Matrix metalloproteinase-1 and Matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis.Stroke 2002;33:2408-12.
50. Zhang B,Dhillon S,Geary I et al.Polymorphisms in matrix metalloproteinase-1,-3,-9,and -12 genes in relation to subarachnodi hemorrhage.Stroke 2001;32:2198-202.
51. Ghilardi G,Biondi ML,Caputo M et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.Clin.Cancer Res 2002;8:3820-3.
52. Zhu Y,Spitz MR,Lei L et al.A single nucleotide polymorphism in the matrix metalloproteinase 1 promoter enhances lung cancer susceptibility.Cancer Res 2001;61:7825-9.
53. Hinoda Y,Okayama N,Takano N et al.Association of functional polymorphisms of matrix metalloproteinase(MMP)-1 and MMP-3 genes with colorectal cancer.Int J Cancer 2002;102:526-9.
54. Okamoto K, Mimura K, Murawaki Y, Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease.J Gastroenterol Hepatol 2005 Jul;20(7):1102-8.
55.梁群,刘群,李长春,等.基质金属蛋白酶-9基因多态性与乙型肝炎肝硬化的关系.J Clin Hepatol 2007 Aug;10(4):229-231.
56. Yoshiji H,Kuriyama S,Yoshii J,et a1.Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats.Hepatology 2001;34:745-750.
57. Paizis G,Gilbert RE,Cooper ME,et a1. Effects of angiotensin IItype 1 receptor blockade on experimental hepatic fibrogenesis.J Hepatol 2001;35:376—385.
58.李乾,张桂英,李新华.血管紧张素Ⅱ与肝纤维化. World Chin J Digestol 2003 March;11(3):334—337.
59.李立新,王宇,张忠涛,等.血管紧张素Ⅱ受体拮抗剂抗纤维化及对Ⅱ型胶原基因表达影响的实验研究.中华肝胆外科杂志2004;1:55-56.
60. Powell EE, Edwards-Smith CJ, Hay JL.et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000 Apr;31(4):828-33.
61.肖凡,魏红山,董庆鸣,樊文梅,刘亚楠.血管紧张素原基因5′端核心启动子区(一6)A～G变异与肝硬化相关性.中华肝脏病杂志2006 Aug;l4(8):609-610.
62. Forresl EH, Thorburn D ,Spence E ,et al. Polymorphism of angiotensin system and the severity of fibrosis in chronic hepatitis Cvirus infection.J Viral Hepat 2005;l2:519—524.
63. Xiao F, Wei H, Song S, Li G,et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol 2006 Sep;21(9):1488-91.
2.张焜和主编.乙肝病毒感染的基础与临床.江西科技出版社1999.
3.于淑丽,龚幼龙,邵瑞太,等.慢性乙肝、乙肝后肝硬化和肝癌的疾病负担.中国公共卫生, 2003,19 (3):280-282.
4.李洪权,李卓,张作文,等.乙型肝炎病毒基因型在无症状感染者、慢性乙肝和肝硬化患者中分布研究.中国预防医学, 2005, 6( 2):213-215.
5. Gressner AM, Schuppan D, Bircher J, et a1. Oxford Textbook of Clinical Hepatology. Oxford: Oxford Medi-cal Publications, 1999: 607-627.
6. He YL, Zhao YR, Zhang SL, et al. Host susceptibility to persistent hepatitis B virus infection. World J Gastroenterol, 2006, 12(30): 4788-4793.
7.林菊生,程元桥,田德英,等. HLA2 DRB1和肿瘤坏死因子α基因多态性与肝硬化的遗传易感性.中华内科杂志, 2002, 41(12):818-821.
8. Xiao F, Wei H, Song S, et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol, 2006, 21(9):1488-1491.
9. Romero-Gomez M, Montes-Cano MA, Otero-Fernandez MA, et al. SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C. Gut, 2004, 53(3):446-450.
10. Burim RV, Canalle R, Martinelli Ade L, et al. Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics. Mutagenesis, 2004,19(4):291-298.
11. Chevillard C, Moukoko CE, Elwali NE, et al. IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). J Immunol, 2003, 171(10):5596-5601.
12. Donaldson P, Agarwal K, Craggs A, et al. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut, 2001, 48(3):397-402
13. The International HapMap Consortium. The international HapMap project. Nature, 2003, 426(6968): 789-796
14. Engle LJ, Simpson CL, Landers JE. Using high-throughput SNP technologies to study cancer. Oncogene, 2006, 25(11):1594-1601.
15. Bataller R, North KE, Brenner DA. Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal. Hepatology, 2003, 37:493-503.
16. Richardson MM, Powell EE, Barrie HD, et al. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet, 2005, 42(7):e45.
17. Wang LD, Zheng S, Liu B, et al. CYP1A1, GSTs and mEH polymorphisms and susceptibility to esophageal carcinoma: Study of population from a high- incidence area in north China. World J Gastroenterol, 2003,9(7):1394-1397.
18. Deng G, Zhou GQ, Zhai Y, et al.Association of estrogen receptorαpolymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology, 2004, 40(2):318-326.
19. Sonzogni L, Silvestri L, De Silvestri A, et al. Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease. Hepatology, 2002, 36(1):195-201.
20.梁群,刘群,李长春,等.基质金属蛋白酶- 9基因多态性与乙型肝炎肝硬化的关系.实用肝脏病杂志, 2007, 10(4):229-231.
21. Xiao F, Wei HS, Song SJ, et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. Hepatology, 2006, 21:1488-1491.
22. Yoshiji H, Kuriyama S, Yoshii J, et a1. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology, 2001, 34:745-750.
23. Paizis G, Gilbert RE, Cooper ME, et a1. Effects of angiotensin IItype 1 receptor blockade on experimental hepatic fibrogenesis.J Hepatol 2001;35:376—385.
24.李乾,张桂英,李新华.血管紧张素Ⅱ与肝纤维化. World Chin J Digestol, 2003, 11(3):334-337.
25.李立新,王宇,张忠涛,等.血管紧张素Ⅱ受体拮抗剂抗纤维化及对Ⅱ型胶原基因表达影响的实验研究.中华肝胆外科杂志, 2004, 1:55-56.
26. Powell EE, Edwards-Smith CJ, Hay JL. et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology, 2000, 31(4):828-33.
27.肖凡,魏红山,董庆鸣,等.血管紧张素原基因5′端核心启动子区(-6)A～G变异与肝硬化相关性.中华肝脏病杂志, 2006 , l4(8):609-610.
28. Forresl EH, Thorburn D, Spence E, et al. Polymorphism of angiotensin system and the severity of fibrosis in chronic hepatitis Cvirus infection. J Viral Hepat, 2005, l2:519-524.
29. Yasuda M, Shimizu I, Shiba M, et al. Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rat. Hepatology, 1999, 29(3):719-727
30. Shimizu I, Mizobuchi Y, Yasuda M, et al. Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut, 1999, 44(2):127-136
31. Smith E P, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med, 1994, 331(16):1056-1061
32. Almog Y, Klein A, Adler R, et al. Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected Hep G-2 cells. Antiviral Res, 1992, 19:285-293
33. Tur-Kaspa R, Shaul Y, Moore DD, et al. The glucocorticoid receptor recognize a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology, 1988, 167:630-633.
34. Deng G, Zhou G, Zhai Y, et al. Association of estrogen receptor a polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology, 2004, 40:318-326.
35. Shearman AM, Cupples LA, Demissie S, et al. Association between estrogen receptor alpha gene variation and cardiovascular disease [J]. JAMA, 2003, 290(17):2263-2270.
36. Kitawaki J, Obayashi H, Ishihara H, et al. Oestrogen receptoralpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata [J]. Hum Reprod, 2001, 16(1):51-55.
37. Kobayashi S, Inoue S, Hosoi T, et al. Association of bone mineral density with polymorphism of the estrogen receptor gene [J]. J Bone Miner Res, 1996, 11(3):306-311.
38. Xie JP, Gong XQ, Tan DM, et al. Estrogen receptor gene polymorphisms and HBV-induced liver cirrhosis. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006, 31(3):379-82.
39. Zhang B, YE S, Herrmann SM, et a1. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosc1erosis [J]. Circulation, 1999, 99(14):1788-94.
40.刘加强,杨富生.关于基质金属蛋白酶9的最新进展[J].牙体牙髓牙周病学杂志, 2005, 15(3):12-15.
41.谢彦华,李里,王立娥,等.基质金属蛋白酶-2,-9与肝纤维化[J].临床肝胆病杂志, 2002, 18(2):82-83.
42.金博,荣佳,岳欣,等.基质金属蛋白酶-2 -9及金属蛋白酶组织抑制物-1基因在病变肝脏的表达[J].海军总医院学报, 2006, 19(4):205-208.
43. Ghilardi G, Biondi ML, MeMonti M, et al. Matrix metalloproteinase-1 and Matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke, 2002, 33:2408-12.
44. Zhang B, Dhillon S, Geary I, et al. Polymorphisms in matrix metalloproteinase-1,-3,-9,and -12 genes in relation to subarachnodi hemorrhage.Stroke 2001;32:2198-202.
45. Ghilardi G, Biondi ML, Caputo M et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility. Clin. Cancer Res , 2002, 8:3820-3.
46. Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase(MMP)-1 and MMP-3 genes with colorectal cancer. Int J Cancer, 2002, 102:526-9.
47. Okamoto K, Mimura K, Murawaki Y, et al. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease. J Gastroenterol Hepatol, 2005, 20(7):1102-8.
48. Guengerich FP. Epoxide hydrolase, properties and metabolic roles. Rev Biochem Toxicol, 1982, 4:5-30.
49. Hassett C, Lin J, Carty CL, et al. Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression. Arch Biochem Biophys, 1997, 337:275-283.
50. Laurenzana EM, Hassett C, Omiecinski CJ. Post-transcriptional regulation of human microsomal epoxide hydrolase. Pharmacogenetics, 1998, 8:157-167.
51. Strickler SM, Dansky LV, Miller MA, et al. Genetic predisposition to phenytoin-induced birth defects. Lancet, 1985, 2:746-749.
52. Sandford AJ, Chagani T, Weir TD, et al. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med, 2000, 163:469-473.
53. Benhamou S, Reinikainen M, Bouchardy C, et al. Association between lung cancer and microsomal epoxide hydrolase genotypes.Cancer Res, 1998, 58:5291-5293.
54. McGlynn KA, Rosvold EA, Lustbader ED, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.Proc Natl Acad Sci USA , 1995, 92:2384-2387.
55. Wong NA, Rae F, Bathgate A, et al. Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. Toxicol Lett, 2000, 115(1):17-22.
56. Truelove AL, Oleksyk TK, Shrestha S, et al. Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome. Int J Immunogenet, 2008, 35(3):255-64.
57. Yang Y, Cheng JZ, Singhal SS, et al. Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem, 2001, 276(22):19220-19230.
58. Rao AV, Shaha C. Role of glutathione s-transferases in oxidative stress-induced male germ cell apoptosis. Free Radical Biol Med, 2000, 29:1015-1027.
59. Whalen R, Boyer TD. Human glutathione S-transferases. Semin Liver Dis, 1998, 18: 345-358.
60. Frenzer A, Butler WJ, Norton ID, et al. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol, 2002, 17:177-182.
61. Rodrigo L, Alvarez V, Rodriguez M, et al. N-acetyltransferase-2, glutathione s-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study. Scand J Gastroenterol, 1999, 34:303-307.
62. Chen SY, Wang LY, Lunn RM, et al. Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls. Int J Cancer, 2002, 99(1):14-21.
63. Zhong S, Tang MW, Yeo W, et al. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res, 2002, 8(4): 1087-1092.
64. Ghobadloo SM, Yaghmaei B, Bakayev V, et al. GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis.J Gastrointest Surg, 2004, 8(4):423-7.
65. Ghobadloo SM, Yaghmaei B, Allameh A, et al. Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers. Clin Biochem, 2006, 39(1):46-9.
1. World Health Organization.Hepatitis B[OB/OL].[2007—4—26].http://who.int/mediacentre/factsheets/fs204/en/index.htm1.
2. Lee WM.Hepatitis B virus infection.N Engl J Med 1997;337:1733-1745.
3.张焜和主编.乙肝病毒感染的基础与临床.江西科技出版社1999.
4.于淑丽,龚幼龙,邵瑞太等.慢性乙肝、乙肝后肝硬化和肝癌的疾病负担.中国公共卫生2003,19 (3):280-282.
5.李洪权,李卓,张作文,等.乙型肝炎病毒基因型在无症状感染者、慢性乙肝和肝硬化患者中分布研究[J].中国预防医学2005;6:213—215.
6. Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. World J Gastroenterol 2003;9 :641–644.
7. Wasmuth HE, Lammert F, Matern S. Genetic risk faction for hepatic fibrosis in chronic liver diseases. Med Klin (Munich) 2003;98(12):754-762.
8. Gressner AM, Schuppan D, Bircher J,Benhamou JP,et a1.Oxford Textbook of Clinical Hepatology.Oxford:Oxford Medi-cal Publications 1999:607-627.
9. Yang Y ,Cheng JZ,Singhal SS, Saini M, Pandya U, Awasthi S, Awasthi YC. Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem 2001; 276(22):19220-19230.
10. Rao AV,Shaha C. Role of glutathione s-transferases in oxidative stress-induced male germ cell apoptosis. Free Radical Biol Med 2000 ;29:1015–1027.
11. Whalen R ,Boyer TD. Human glutathione S-transferases. Semin Liver Dis 1998;18 : 345–358.
12. Cabre M, Camps J, Paternain JL, Ferre N, Joven J. Time course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. Hepatology 1999 ;29 :664–669.
13. Frenzer A, Butler WJ, Norton ID, Wilson JS, Apte MV, Pirola RC,et al. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol 2002;17:177–182.
14. Rodrigo L, Alvarez V, Rodriguez M, Perez R, Alvarez R,Coto E. N-acetyltransferase-2, glutathione s-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study. Scand J Gastroenterol 1999; 34 :303–307.
15. Chen SY, Wang LY, Lunn RM, Tsai WY, Lee PH, Lee CS, et al. Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls. Int J Cancer 2002 May 1;99(1):14–21.
16. Zhong S,Tang MW, Yeo W,Liu C, Lo YM, Johnson PJ. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res. 2002 Apr;8 (4): 1087–1092.
17. Ghobadloo SM, Yaghmaei B, Bakayev V,et al.GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis.J Gastrointest Surg 2004 May-Jun;8(4):423-7.
18. Ghobadloo SM, Yaghmaei B, Allameh A, et al. Polymorphisms of glutathione S-transferase M1, T1, and P1 in patients with HBV-related liver cirrhosis, chronic hepatitis, and normal carriers. Clin Biochem 2006 Jan;39(1):46-9.
19. Guengerich FP. Epoxide hydrolase,properties and metabolic roles. Rev Biochem Toxicol 1982;4:5-30.
20. Omiecinski CJ,Aicher L,Holubkov R,Checkoway H. Human peripheral lymphocytes as indicators of microsomal epoxide hydrolase activity in liver and lung Pharmacogenetics 1993;3:150-158.
21. Hassett C,Lin J.Carty CL,Laurenzana EM,Omiecinski CJ.Human hepatic microsomal epoxide hydrolase:comparative analysis of polymorphic expression.Arch Biochem Biophys 1997;337:275-283.
22. Hassett C,Aicher L,Sidhu JS,Omiecinski CJ.Human microsomal epoxide hydrolase;genetic polymorphism and functional expression in vitro of amino acid variants.Hum Mol Genet 1994;3:412-428.
23. Omiecinski CJ,Hassett C,Hosagrahara V.Epoxide hydrolase-polymorphism and role in toxicology.Toxicol Lett 2000;112:365-370.
24. Laurenzana EM,Hassett C,Omiecinski CJ.Post-transcriptional regulation of human microsomal epoxide hydrolase.Pharmacogenetics 1998;8:157-167.
25. Strickler SM,Dansky LV,Miller MA,Seni MH,Andermann E,Spielberg SP.Genetic predisposition to phenytoin-induced birth defects.Lancet 1985;2:746-749.
26. Smith CAD,Harrison DJ.Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema.Lancet 1997;350:630-633.
27. Sandford AJ,Chagani T,Weir TD,Connett JE,Anthonisen NR,Pare PD.Susceptibility genes for rapid decline of lung function in the lung health study.Am J Respir Crit Care Med 2000;163:469-473.
28. Benhamou S,Reinikainen M,Bouchardy C,Dayer P,Hirvonen A.Association between lung cancer and microsomal epoxide hydrolase genotypes.Cancer Res 1998;58:5291-5293.
29. Gaedigk A,Spielberg SP,Grant DM.Characterization of the microsomal epoxide hydrolase in patients with anticonvulsant adverse drug reactions.Pharmacogenetics 1994;4:142-153.
30. McGlynn KA,Rosvold EA,Lustbader ED,Hu Y,Clapper ML,Zhou T,Wild CP,et al.Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.Proc Natl Acad Sci U S A 1995;92:2384-2387.
31. Raaka S,Hassett C,Omiecinski CJ. Human microsomal epoxide hydrolase:5′-flankingregion genetic polymorphisms. Carcinogenesis 1998;19:387-393.
32. Wong NA, Rae F, Bathgate A,et al. Polymorphisms of the gene for microsomal epoxide hydrolase and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a Caucasian population. Toxicol Lett 2000 Apr 10;115(1):17-22
33. Sonzogni L, Silvestri L, Silvestri AD, et al.Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease. Hepatology 2002 Jul;36(1):195-201
34. Yasuda M,Shimizu I,Shiba M,et al.Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rat. Hepatology 1999;29(3):719-727
35. Shimizu I,Mizobuchi Y,Yasuda M,et al.Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut 1999;44(2):127-136.
36. SmithE P,Boyd J,Frank GR,Takahashi H,Cohen RM,SpeckerB, William s TC,Lubahn DB,Korach KS. Estrogen resistance caused by a mutation in the estrogen—receptor gene in a man.N Engl J Med 1994;331(16):1056—1061
37. Shearman AM,Cupples LA,Demissie S,et al .Association between estrogen receptor alpha gene variation and cardiovascular disease[J].JAMA.2003,290(17):2263-2270.
38. Kitawaki J,Obayashi H,Ishihara H,et al.Oestrogen receptoralpha gene polymorphism is associated with endometriosis,adenomyosis and leiomyomata [J].Hum Reprod 2001;16(1):51-55.
39. Kobayashi S,Inoue S,Hosoi T,er al. Association of bone mineral density with polymorphism of the estrogen receptor gene [J].J Bone Miner Res 1996;11(3):306-311.
40. Almog Y.Klein A,Adler R,Laub O,Tur—Kaspa R.Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected Hep G-2 cells.Antiviral Res 1992;19:285—293
41. Tur-Kaspa R,Shaul Y,Moore DD,Burk RD,Okret S,Poellinger L,Shafritz DA.The glucocorticoid receptor recognize a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer.Virology 1988;167:630-633.
42. Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F. Association of estrogen receptor a polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004;40:318-326.
43. Xie JP, Gong XQ, Tan DM, Liu F, Zhou JL.Estrogen receptor gene polymorphisms and HBV-induced liver cirrhosis.Zhong Nan Da Xue Xue Bao Yi Xue Ban 2006 Jun;31(3):379-82.
44. Nagase H,Woessner JF,Matrix metalloproteinases.J Biol Chem 1999;274:21491-4.
45.谢彦华,李里,王立娥,等.基质金属蛋白酶-2-9及金属蛋白酶与肝纤维化[J].临床肝胆病杂志2002;18(2):82-83.
46. Iredak W,Benyon R C,Rctering J,et al.Mechanisms of spontaneous resolution of rat liver fibrosis,hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibition[J].J Clin Invest 1998;102(8):538-549.
47.王爱民,王宝恩,杨跃伟,等.慢性肝病金属蛋白酶组织抑制因子-1基因表达的研究.Chin J Dig 1999; 19:59-60.
48. Ye S,Watts GF,Mandalia S et al.Preliminary report:genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis.Brit.Heart J 1995;73:209-15.
49. Ghilardi G,Biondi ML,MeMonti M et al.Matrix metalloproteinase-1 and Matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis.Stroke 2002;33:2408-12.
50. Zhang B,Dhillon S,Geary I et al.Polymorphisms in matrix metalloproteinase-1,-3,-9,and -12 genes in relation to subarachnodi hemorrhage.Stroke 2001;32:2198-202.
51. Ghilardi G,Biondi ML,Caputo M et al.A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.Clin.Cancer Res 2002;8:3820-3.
52. Zhu Y,Spitz MR,Lei L et al.A single nucleotide polymorphism in the matrix metalloproteinase 1 promoter enhances lung cancer susceptibility.Cancer Res 2001;61:7825-9.
53. Hinoda Y,Okayama N,Takano N et al.Association of functional polymorphisms of matrix metalloproteinase(MMP)-1 and MMP-3 genes with colorectal cancer.Int J Cancer 2002;102:526-9.
54. Okamoto K, Mimura K, Murawaki Y, Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease.J Gastroenterol Hepatol 2005 Jul;20(7):1102-8.
55.梁群,刘群,李长春,等.基质金属蛋白酶-9基因多态性与乙型肝炎肝硬化的关系.J Clin Hepatol 2007 Aug;10(4):229-231.
56. Yoshiji H,Kuriyama S,Yoshii J,et a1.Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats.Hepatology 2001;34:745-750.
57. Paizis G,Gilbert RE,Cooper ME,et a1. Effects of angiotensin IItype 1 receptor blockade on experimental hepatic fibrogenesis.J Hepatol 2001;35:376—385.
58.李乾,张桂英,李新华.血管紧张素Ⅱ与肝纤维化. World Chin J Digestol 2003 March;11(3):334—337.
59.李立新,王宇,张忠涛,等.血管紧张素Ⅱ受体拮抗剂抗纤维化及对Ⅱ型胶原基因表达影响的实验研究.中华肝胆外科杂志2004;1:55-56.
60. Powell EE, Edwards-Smith CJ, Hay JL.et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000 Apr;31(4):828-33.
61.肖凡,魏红山,董庆鸣,樊文梅,刘亚楠.血管紧张素原基因5′端核心启动子区(一6)A～G变异与肝硬化相关性.中华肝脏病杂志2006 Aug;l4(8):609-610.
62. Forresl EH, Thorburn D ,Spence E ,et al. Polymorphism of angiotensin system and the severity of fibrosis in chronic hepatitis Cvirus infection.J Viral Hepat 2005;l2:519—524.
63. Xiao F, Wei H, Song S, Li G,et al. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol 2006 Sep;21(9):1488-91.