中国北方汉族人群FAS（-1377G→A和-670A→G）、FASL（-844C→T）及CASP8（-652 6N ins→del）基因多态性与HBV感染不同结局的关联研究
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摘要
人类感染乙型肝炎病毒(hepatitis B virus,HBV)后有不同的临床结局,其原因可能与宿主的免疫系统密切相关。T细胞反应,尤其是细胞毒性T淋巴细胞(cytotoxicT lymphocyte,CTL)的反应,在病毒清除及感染后进程中起了重要作用。CTL主要通过穿孔素和Fas/Fas配体(FasL)介导的凋亡通路杀伤目标。所以研究Fas/FasL凋亡通路的基因多态性与HBV感染结局的关系,对于探究HBV感染不同结局的原因可能有重要意义。
方法:本研究采用病例对照的方法,在中国北方汉族人群中选取慢性乙型肝炎病人207例,非活动性HBV携带者203例,HBV自限性感染者150例作为研究对象,采用限制性片段长度多态性法检测其FAS(-1377G→A和-670A→G)、FASL(-844C→T)及CASP8(-652 6N ins→del)基因多态性,分析遗传因素与环境因素的交互作用,以探讨其与HBV感染不同结局的关系。数据使用非条件logistic回归进行分析,计算比值比(odds ratio,OR)和95%置信区间(95%confidence intervals,95%CI)。统计检验均为双侧。
结果:
1、慢性乙型肝炎患者与非活动性HBV携带者两组比较,非活动性HBV携带者中携带CASP8-652 6N del/del基因型的频率,显著高于慢性乙型肝炎患者的携带频率,携带此基因型者降低发展成为慢性乙肝的风险(OR=0.03,95%CI:0.01-0.06)。慢性乙型肝炎患者与HBV自限性感染者两组比较,HBV自限性感染者中携带CASP8-652 6N ins/del基因型及CASP8-652 6N del/de基因型的频率,显著高于慢性乙型肝炎患者的携带频率,携带此基因型者降低发展成为慢性乙肝的风险(OR=0.22,95%CI:0.09-0.52;OR=0.02,95%CI:0.01-0.04)。
2、将慢性乙型肝炎组与非活动性HBV携带者合并作为病例组,将自限性感染作为对照组分析结果显示,自限性感染组中的FAS-1377GG基因型的频率,显著高于慢性乙型肝炎组与非活动性HBV携带者的携带频率,携带此基因者降低发展为慢性乙肝和HBV携带者的风险(OR=0.58,95%CI:0.35-0.94;P=0.028)。
3、FAS-1377与CASP8-652基因-基因交互作用对乙肝病毒感染不同结局的影响没有检测到。
4、采用病例对照分析CASP8-652 6N del等位基因与吸烟、饮酒在慢性乙肝发生过程中可能存在正交互作用。
结论:凋亡通路基因FAS-1377与CASP8-652基因多态性与乙型肝炎病毒感染后的不同临床结局相关。
The clinical outcomes of hepatitis B virus(HBV) infection are extremely variable, and might be associated with genetic differences of the host.It is suggested that that T-cell responses,especially the responses of cytotoxic T lymphocytes(CTLs),play a central role in viral clearance.CTLs kill cells through perforin and Fas/Fas ligand (FasL)-mediated death pathways.The polymorphisms of apoptosis pathway genes might be associated with the outcomes of HBV infection.
Methods:Genotypes were determined in 207 chronic HB patients,203 chronic inactive HBV carriers and 150 spontaneous recovery subjects by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Odds ratios(OR) and 95%confidence intervals(95%CI) were estimated by logistic regression,and all statistical tests were two sided.
Results:
1.The frequency of CASPS-652 6N del/del genotype in inactive HBV carriers was significantly higher than that in chronic HB.HBV carriers having CASP8-652 6N del/del genotype had an OR of 0.03(95%CI:0.01-0.06) for developing Chronic HB comparing with subjects having CASP8-652 6N ins/ins genotype.The frequencies of CASPS-652 6N ins/del and CASP8-652 6N del/del genotypes in spontaneous recovery subjects were significantly higher than those in chronic HB.Spontaneous recovery subjects having CASPS-652 6N ins/del and CASPS-652 6N del/del genotype had an OR of 0.22(95%CI: 0.09-0.52) or 0.02(95%CI:0.01-0.04),respectively,for developing Chronic HB comparing with subjects having CASPS-652 6N ins/ins genotype.
2.The frequency of FAS-1377GG genotype in Chronic HB combined with inactive HBV carriers was significantly higher that in spontaneous recovery subjects. Spontaneous recovery subjects having FAS-1377GG genotype had an OR of 0.58(95%CI: 0.35-0.94) for developing chronic HB and chronic inactive HB carriers comparing with subjects having FAS-1377AA or GA genotypes.
3.No gene-gene interaction between the FAS-1377 and CASP8-652 variants were detected in reducing the risk of chronic HB.
4.A multiplicative joint effect between the CASP8-652 6N del/del genotype and smoking or drinking in intensifying risk of chronic HB was also evident.
Conclusions:These results suggest that genetic variations in the death pathway genes FAS and CASP8 are involved in different clinical outcomes of HBV infection.
方法:本研究采用病例对照的方法,在中国北方汉族人群中选取慢性乙型肝炎病人207例,非活动性HBV携带者203例,HBV自限性感染者150例作为研究对象,采用限制性片段长度多态性法检测其FAS(-1377G→A和-670A→G)、FASL(-844C→T)及CASP8(-652 6N ins→del)基因多态性,分析遗传因素与环境因素的交互作用,以探讨其与HBV感染不同结局的关系。数据使用非条件logistic回归进行分析,计算比值比(odds ratio,OR)和95%置信区间(95%confidence intervals,95%CI)。统计检验均为双侧。
结果:
1、慢性乙型肝炎患者与非活动性HBV携带者两组比较,非活动性HBV携带者中携带CASP8-652 6N del/del基因型的频率,显著高于慢性乙型肝炎患者的携带频率,携带此基因型者降低发展成为慢性乙肝的风险(OR=0.03,95%CI:0.01-0.06)。慢性乙型肝炎患者与HBV自限性感染者两组比较,HBV自限性感染者中携带CASP8-652 6N ins/del基因型及CASP8-652 6N del/de基因型的频率,显著高于慢性乙型肝炎患者的携带频率,携带此基因型者降低发展成为慢性乙肝的风险(OR=0.22,95%CI:0.09-0.52;OR=0.02,95%CI:0.01-0.04)。
2、将慢性乙型肝炎组与非活动性HBV携带者合并作为病例组,将自限性感染作为对照组分析结果显示,自限性感染组中的FAS-1377GG基因型的频率,显著高于慢性乙型肝炎组与非活动性HBV携带者的携带频率,携带此基因者降低发展为慢性乙肝和HBV携带者的风险(OR=0.58,95%CI:0.35-0.94;P=0.028)。
3、FAS-1377与CASP8-652基因-基因交互作用对乙肝病毒感染不同结局的影响没有检测到。
4、采用病例对照分析CASP8-652 6N del等位基因与吸烟、饮酒在慢性乙肝发生过程中可能存在正交互作用。
结论:凋亡通路基因FAS-1377与CASP8-652基因多态性与乙型肝炎病毒感染后的不同临床结局相关。
The clinical outcomes of hepatitis B virus(HBV) infection are extremely variable, and might be associated with genetic differences of the host.It is suggested that that T-cell responses,especially the responses of cytotoxic T lymphocytes(CTLs),play a central role in viral clearance.CTLs kill cells through perforin and Fas/Fas ligand (FasL)-mediated death pathways.The polymorphisms of apoptosis pathway genes might be associated with the outcomes of HBV infection.
Methods:Genotypes were determined in 207 chronic HB patients,203 chronic inactive HBV carriers and 150 spontaneous recovery subjects by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Odds ratios(OR) and 95%confidence intervals(95%CI) were estimated by logistic regression,and all statistical tests were two sided.
Results:
1.The frequency of CASPS-652 6N del/del genotype in inactive HBV carriers was significantly higher than that in chronic HB.HBV carriers having CASP8-652 6N del/del genotype had an OR of 0.03(95%CI:0.01-0.06) for developing Chronic HB comparing with subjects having CASP8-652 6N ins/ins genotype.The frequencies of CASPS-652 6N ins/del and CASP8-652 6N del/del genotypes in spontaneous recovery subjects were significantly higher than those in chronic HB.Spontaneous recovery subjects having CASPS-652 6N ins/del and CASPS-652 6N del/del genotype had an OR of 0.22(95%CI: 0.09-0.52) or 0.02(95%CI:0.01-0.04),respectively,for developing Chronic HB comparing with subjects having CASPS-652 6N ins/ins genotype.
2.The frequency of FAS-1377GG genotype in Chronic HB combined with inactive HBV carriers was significantly higher that in spontaneous recovery subjects. Spontaneous recovery subjects having FAS-1377GG genotype had an OR of 0.58(95%CI: 0.35-0.94) for developing chronic HB and chronic inactive HB carriers comparing with subjects having FAS-1377AA or GA genotypes.
3.No gene-gene interaction between the FAS-1377 and CASP8-652 variants were detected in reducing the risk of chronic HB.
4.A multiplicative joint effect between the CASP8-652 6N del/del genotype and smoking or drinking in intensifying risk of chronic HB was also evident.
Conclusions:These results suggest that genetic variations in the death pathway genes FAS and CASP8 are involved in different clinical outcomes of HBV infection.
引文
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8.Cacciola I,Cerenzia G,Pollicino T,SquadritoG,Castellaneta S,Zanetti AR,Mieli-Vergani G,Raimondo G:Genomic heterogeneity of hepatitis B virus(HBV) and outcome of perinatal HBV infection.J Hepatol 2002;36:426-432.
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1.Nagata,S.,and Golstein,P.:The Fas death factor,Science.1995;267:1449-1456.
2.Nagata S:Apoptosis by death factor.Cell 1997;88:355-365.
3.Suda T,Okazaki T,Naito Y,Yokota T,Arai N,Ozaki S,Nakao K,Nagata S:Expression of the Fas ligand in cells of T cell lineage.J Immunol 1995;154:3806-3813.
4.Lowin B,Hahne M,Mattmann C et al.Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lyric pathway.Science 1994;370:650-652
5.Berke G.The CTL's kiss of death.Cell.1995 Apr 7;81(1):9-12.Review.
6.Huang QR,Morris D,Manolios N.Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas(CD95) gene.Mol Immunol 1997;34;577-582
7.Sibley K,Rollinson S,Allan JM et al.Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia.Cancer Res 2003;63;4327-4330
8.Kanemitsu S,Ihara K,Saifddin A et al.A functional polymorphism in Fas(CD95/APO-1) gene promoter associated with systemic lupus erythematosus.J Rheumatol 2002;29:1183-1188
9.26.Wu J,Metz C,Xu X et al.A novel polymorphic CAAT/enhancer-binding protein-element in the FasL gene promoter alters Fas ligand expression:a candidate background gene in African American systemic lupus erythematosus patients.J Immunol 2003;170:132-138
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13.O'Connell J,O'Sullivan GC,Collins JK,Shanahan F.The Fas counterattack:Fas-mediated T cell killing by colon cancer cells expressing Fas ligand.J Exp Med 1996;184:1075-1082.
14.SunT,Miao X,Zhang X,TanW,Xiong P,Lin D.Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma.J Natl Cancer Inst 2004;96:1030-1016.
15.Zhang X,Miao X,SunT,et al.Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer.JMed Genet 2005;42:479-484:
16.Wang LE,Cheng L,Spitz MR,Wei Q.Fas A670G polymorphism,apoptotic capacity in lymphocyte cultures,and risk of lung cancer.Lung Cancer 2003;42:1-8.
17.Lai HC,Sytwu HK,Sun CA,Yu MH,Yu CP,Liu HS,Chang CC,Chu TY:Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis.Int J Cancer.2003 Jan 10;103(2):221-5.
18.Lai HC,Lin WY,Lin YW,Chang CC,Yu MH,Chen CC,Chu TY:Genetic polymorphisms of FAS and FASL (CD95/CD95L) genes in cervical carcinogenesis:An analysis of haplotype and gene-gene interaction.Gynecol Oncol.2005 Oct;99(1):113-8.
19.SunT,ZhouY,Li H,et al.FASL -844C polymorphismis associatedwith increased activation-induced T cell death and risk of ccrvical cancer.J Exp Med 2005;202:967-974.
20.Zhang B,Sun T,Xue L,et al.Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.Carcinogenesis 2007;28:1067-1073.
21.Zhang Z,Wang LE,Sturgis EM,et al.Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck.Clin Cancer Res 2006;12:5596-5602.
22.Li C,Larson D,Zhang Z,et al.Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma.Pharmacogenet Genomics 2006;16:253-263.
23.Yang M,Sun T,Wang L,Yu D,Zhang X,Mian X,Liu J,Zhao D,Li H,Tan W,Lin D.:Functional variants in cell death pathway genes and risk of pancreatic cancer.Clin Cancer Res.2008 May 15;14(10):3230-6.
24.Hsu PI,Lu PJ,Wang EM,Ger LP,Lo GH,Tsay FW,Chen TA,Yang HB,Chen HC,Lin WS,Lai KH.Polymorphisms of death pathway genes FAS and FASL and risk of premalignant gastric lesions.Anticancer Res.2008 Jan-Feb;28(1A):97-103.
25.Hsu PI,Lu PJ,Wang EM,Ger LP,Lo GH,Tsay FW,Chen TA,Yang HB,Chen HC,Lin WS,Lai KH.Polymorphisms of death pathway genes FAS and FASL and risk of premalignant gastric lesions.Anticancer Res.2008Jan-Feb;28(1A):97-103.
26.Jung YJ,Kim YJ,Kim LH,Lee SO,Park BL,Shin HD,Lee HS.Putative association of Fas and FasL gene polymorphisms with clinical outcomes of hepatitis B virus infection.Intervirology.2007;50(5):369-76.
2.戴志澄,祁国明主编.中国病毒肝炎血清流行病学调查(上卷)P39-58,1997,科学技术出版社
3.Anna S.F.:Chronic hepatitis B.N Engl J Med 2002;Vol.346:1682-1683.
4.Niederau C,Heintges T,lange S,Goldmann G,Niederau CM,Mohr L,Haussinger D.Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med 1996;334:1422-1427
5.Fattovich G:Natural history and prognosis of hepatitis B.Semin Liver Dis 2003;23:47-58.
6.Stevens CE,Beasley RP,Tsui J,Lee WC:Vertical transmission of hepatitis B antigen in Taiwan.N Engl J Med 1975;292:771-774.
7.Lok AS,Lai CL,Wu PC,Wong VC,Yeoh EK,Lin HJ:Hepatitis B virus infection in Chinese families in Hong Kong.Am J Epidemiol 1987;126:492-499.
8.Cacciola I,Cerenzia G,Pollicino T,SquadritoG,Castellaneta S,Zanetti AR,Mieli-Vergani G,Raimondo G:Genomic heterogeneity of hepatitis B virus(HBV) and outcome of perinatal HBV infection.J Hepatol 2002;36:426-432.
9.Chisari FV,Ferrari C:Hepatitis B virus immunopathogenesis.Annu Rev Immunol 1995;13:29-60.
10.Koziel MJ.Immunology of viral hepatitis.Am J med 1996;100:98-109
11.Chisari FV:Cytotoxic T cells and viral hepatitis.J Clin Invest 1997;99:1472-1477.
12.Don Ganem,Alfred M.Prince:Hepatitis B virus infection-natual history and clinical consequences.N Engl J Med 2004;350:1118-1129.
13.Lowin B,Hahne M,Mattmann C et al.Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathway.Science 1994;370:650-652
14.Nagata,S.,and Golstein,P.:The Fas death factor.Science.1995;267:1449-1456.
15.Nagata S:Apoptosis by death factor.Cell 1997;88:355-365.
16.Suda T,Okazaki T,Naito Y,Yokota T,Arai N,Ozaki S,Nakao K,Nagata S:Expression of the Fas ligand in cells of T cell lineage.J Immunol 1995;154:3806-3813.
17.Hayashi N,Mita E.:Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis.J Viral Hepat.1999 Sep;6(5):357-65.
18.Patel T,Steer CJ,Gores GJ.Apoptosis and the liver:a mechanism of disease,growth regulation,and carcinogenesis.Hepatololgy 1999;30:811-815
19.Mochizuki K,Hayashi N,Kiramatsu N et al.Fas antigen expression in liver tissues of patients with chronic Hepatitis B.J Hepatol 1996;24:1-7
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