干扰素β启动子刺激因子1基因多态性与HBeAg阳性慢性乙型肝炎患者聚乙二醇干扰素α治疗应答的关系
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摘要
目的探讨干扰素β启动子刺激因子(IPS)-1基因多态性与HBeAg阳性慢性乙型肝炎患者聚乙二醇干扰素(PEGIFN)α治疗应答的关系。方法收集2008年1月-2012年12月在上海瑞金医院感染科就诊的212例接受PEG-IFN单药治疗48周的HBeAg阳性慢性乙型肝炎患者,采集其外周血,提取基因组DNA,并应用时间飞行质谱技术(MassARRAY)检测IPS-1基因的10个Tag-SNP位点多态性。运用卡方检验对2组等位基因频率和基因型分布情况进行分析,应用非条件性二元Logistic回归分析方法分析SNP位点、单体型与PEG-IFN疗效的关系。结果 212例患者中,应答率为34.9%(74例),其中HBV基因C型117例,B型95例。研究发现有4个SNP位点(rs2326369、rs2464、rs6515831、rs16989000)的基因型分布在2组之间差异有统计学意义(P<0.05)。在多因素分析中,校正了性别、年龄、HBV基因型、家族史、基线HBV DNA水平及基线ALT水平后,发现3个SNP位点(rs2326369、rs6515831、rs2464)与PEG-IFN应答独立相关。其中(1)rs2326369 CC型与NR相关(OR=0.51,95%CI:0.28~0.92,P=0.026);(2)rs6515831 TT型与R相关(OR=2.08,95%CI:1.12~3.86,P=0.020);(3)rs2464 CC型与R相关(OR=2.33,95%CI:1.24~4.37,P=0.009)。此外,还发现了2个单体域(block),block1:rs16989000-rs6515831;block2:rs7272495-rs16989022-rs2464。多因素分析发现Block2中的单体型AAC型与R显著相关(OR=2.05,95%CI:1.09~3.87,P=0.026)。结论 IPS-1基因多态性与HBeAg阳性慢性乙型肝炎患者对PEG-IFN治疗的应答密切相关。对于接受PEG-IFN治疗的慢性乙型肝炎患者,检测IPS-1基因型可能有一定的疗效预测价值。
Objective To investigate whether interferon- β promoter stimulator 1(IPS- 1) gene polymorphisms could affect the treatment response to peginterferon alpha(PEG- IFN) in patients with HBeAg- positive chronic hepatitis B(CHB).Methods A total of 212HBeAg- positive CHB patients treated with PEG- IFN monotherapy for 48 weeks were enrolled from the department of infectious diseases of Ruijin hospital in this study from January 2008 to December 2012.We collected peripheral blood from patients and extracted total genomic DNA.Genotype analysis was performed for 10 tag single nucleotide polymorphisms(SNPs) in IPS- 1 gene using the Sequenom MassArray system.Response was defined as cases showing hepatitis B virus(HBV) DNA level < 200 IU /ml,HBeAg seroconversion,and normal aminotransferase(ALT) levels after 48- week PEG- IFN therapy.The chi- square test was conducted to analyze the allele frequency and genotype distribution of IPS- 1 in both the response(R) and non- response(NR) groups.Binary logistic regression modeling was used to analyze the association of SNPs and haplotypes of IPS- 1 with treatment response.Results Of all the 212 patients,95(44.8%) were infected with HBV genotype B and 117(55.2%) with HBV genotype C.There was a total response rate of 34.9%(74 /212).Significant differences in genotype distributions of four SNPs(rs2326369,rs2464,rs6515831,and rs16989000) were observed between the R and NR groups(P < 0.05).In multivariate analysis,three SNPs(rs2326369,rs6515831,and rs2464) were found to be independently associated with PEG- IFN efficacy after adjustment for sex,age,HBV genotype,family history,and baseline levels of HBV DNA and ALT:(1)rs2326369 CC genotype was independently associated with NR(OR = 0.51,95% CI:0.28- 0.92,P = 0.026);(2) rs6515831 TT genotype was independently associated with R(OR = 2.08,95% CI:1.12- 3.86,P = 0.020);(3) rs2464 CC genotype was independently associated with R(OR = 2.33,95% CI:1.24- 4.37,P = 0.009).Furthermore,two blocks were identified in this study,with block 1formed by rs16989000 and rs6515831 and block 2 formed by rs7272495,rs16989022,and rs2464.In multivariate analysis,haplotype AAC of block 2 was independently associated with R(OR = 2.05,95% CI:1.09- 3.87,P = 0.026).Conclusion Our study suggested that genetic variations in IPS- 1 are associated with the treatment response to PEG- IFN in HBeAg- positive CHB patients.For CHB patients treated with PEG- IFN,IPS- 1 genotyping may have a certain predictive value for curative effect.
Objective To investigate whether interferon- β promoter stimulator 1(IPS- 1) gene polymorphisms could affect the treatment response to peginterferon alpha(PEG- IFN) in patients with HBeAg- positive chronic hepatitis B(CHB).Methods A total of 212HBeAg- positive CHB patients treated with PEG- IFN monotherapy for 48 weeks were enrolled from the department of infectious diseases of Ruijin hospital in this study from January 2008 to December 2012.We collected peripheral blood from patients and extracted total genomic DNA.Genotype analysis was performed for 10 tag single nucleotide polymorphisms(SNPs) in IPS- 1 gene using the Sequenom MassArray system.Response was defined as cases showing hepatitis B virus(HBV) DNA level < 200 IU /ml,HBeAg seroconversion,and normal aminotransferase(ALT) levels after 48- week PEG- IFN therapy.The chi- square test was conducted to analyze the allele frequency and genotype distribution of IPS- 1 in both the response(R) and non- response(NR) groups.Binary logistic regression modeling was used to analyze the association of SNPs and haplotypes of IPS- 1 with treatment response.Results Of all the 212 patients,95(44.8%) were infected with HBV genotype B and 117(55.2%) with HBV genotype C.There was a total response rate of 34.9%(74 /212).Significant differences in genotype distributions of four SNPs(rs2326369,rs2464,rs6515831,and rs16989000) were observed between the R and NR groups(P < 0.05).In multivariate analysis,three SNPs(rs2326369,rs6515831,and rs2464) were found to be independently associated with PEG- IFN efficacy after adjustment for sex,age,HBV genotype,family history,and baseline levels of HBV DNA and ALT:(1)rs2326369 CC genotype was independently associated with NR(OR = 0.51,95% CI:0.28- 0.92,P = 0.026);(2) rs6515831 TT genotype was independently associated with R(OR = 2.08,95% CI:1.12- 3.86,P = 0.020);(3) rs2464 CC genotype was independently associated with R(OR = 2.33,95% CI:1.24- 4.37,P = 0.009).Furthermore,two blocks were identified in this study,with block 1formed by rs16989000 and rs6515831 and block 2 formed by rs7272495,rs16989022,and rs2464.In multivariate analysis,haplotype AAC of block 2 was independently associated with R(OR = 2.05,95% CI:1.09- 3.87,P = 0.026).Conclusion Our study suggested that genetic variations in IPS- 1 are associated with the treatment response to PEG- IFN in HBeAg- positive CHB patients.For CHB patients treated with PEG- IFN,IPS- 1 genotyping may have a certain predictive value for curative effect.
引文
[1]REHERMANN B.Chronic infections with hepatotropic viruses:mechanisms of impairment of cellular immune responses[J].Semin Liver Dis,2007,27(2):152-160.
[2]KAWAI T,TAKAHASHI K,SATO S,et al.IPS-1,an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction[J].Nat Immunol,2005,6(10):981-988.
[3]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B(2010 version)[J].J Clin Hepatol,2011,27(1):Ⅰ-ⅩⅥ.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J].临床肝胆病杂志,2011,27(1):Ⅰ-ⅩⅥ.
[4]BARRETT JC,FRY B,MALLER J,et al.Haploview:analysis and visualization of LD and haplotype maps[J].Bioinformatics,2005,21(2):263-265.
[5]GABRIEL SB,SCHAFFNER SF,NGUYEN H,et al.The structure of haplotype blocks in the human genome[J].Science,2002,296(5576):2225-2229.
[6]MEYLAN E,TSCHOPP J,KARIN M.Intracellular pattern recognition receptors in the host response[J].Nature,2006,442(7098):39-44.
[7]KUMAR H,KAWAI T,KATO H,et al.Essential role of IPS-1 in innate immune responses against RNA viruses[J].J Exp Med,2006,203(7):1795-1803.
[8]BARIL M,RACINE ME,PENIN F,et al.MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease[J].J Virol,2009,83(3):1299-1311.
[9]DENG L.Review of recent research progress in correlating HBV genotypes with efficacy of antiviral treatments[J].J Clin Hepatol,2012,28(6):469-473.(in Chinese)邓乐.乙型肝炎病毒基因型与抗病毒药物疗效关系的研究进展[J].临床肝胆病杂志,2012,28(6):469-473.
[10]BALACHANDRAN S,THOMAS E,BARBER GN.A FADD-dependent innate immune mechanism in mammalian cells[J].Nature,2004,432(7015):401-405.
[11]TAKAHASHI K,KAWAI T,KUMAR H,et al.Roles of caspase-8and caspase-10 in innate immune responses to double-stranded RNA[J].J Immunol,2006,176(8):4520-4524.
[12]BUSTER EH,HANSEN BE,LAU GK,et al.Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa[J].Gastroenterology,2009,137(6):2002-2009.
[13]SONNEVELD MJ,RIJCKBORST V,BOUCHER CA,et al.Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline[J].Hepatology,2010,52(4):1251-1257.
[14]TSENG TC,YU ML,LIU CJ,et al.Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-α-2a therapy[J].Antivir Ther,2011,16(5):629-637.
[15]HUANG YX,MA LN,CHEN XY,et al.Genetic polymorphisms of MxA protein and eIF-2a-reg2 and their responses to interferon treatment in patients with chronic hepatitis B[J].Chin J Hpeatol,2007,15(3):187-191.(in Chinese)黄雁翔,马丽娜,陈新月,等.粘病毒抵抗蛋白A和真核细胞起始因子2α调节区2基因多态性与慢性乙型肝炎干扰素治疗效果的相关性[J].中华肝脏病杂志,2007,15(3):187-191.
[16]WU X,ZHU X,ZHU S,et al.A pharmacogenetic study of polymorphisms in interferon pathway genes and response to interferonalpha treatment in chronic hepatitis B patients[J].Antiviral Res,2009,83(3):252-256.
[17]KING JK,YEH SH,LIN MW,et al.Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients:A pilot study[J].Hepatology,2002,36(6):1416-1424.
[18]LAMPERTICO P,VIGANOM,CHERONI C,et al.IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B[J].Hepatology,2013,57(3):890-896.
[19]SONNEVELD MJ,WONG VW,WOLTMAN AM,et al.Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B[J].Gastroenterology,2012,142(3):513-520.
[2]KAWAI T,TAKAHASHI K,SATO S,et al.IPS-1,an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction[J].Nat Immunol,2005,6(10):981-988.
[3]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B(2010 version)[J].J Clin Hepatol,2011,27(1):Ⅰ-ⅩⅥ.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J].临床肝胆病杂志,2011,27(1):Ⅰ-ⅩⅥ.
[4]BARRETT JC,FRY B,MALLER J,et al.Haploview:analysis and visualization of LD and haplotype maps[J].Bioinformatics,2005,21(2):263-265.
[5]GABRIEL SB,SCHAFFNER SF,NGUYEN H,et al.The structure of haplotype blocks in the human genome[J].Science,2002,296(5576):2225-2229.
[6]MEYLAN E,TSCHOPP J,KARIN M.Intracellular pattern recognition receptors in the host response[J].Nature,2006,442(7098):39-44.
[7]KUMAR H,KAWAI T,KATO H,et al.Essential role of IPS-1 in innate immune responses against RNA viruses[J].J Exp Med,2006,203(7):1795-1803.
[8]BARIL M,RACINE ME,PENIN F,et al.MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease[J].J Virol,2009,83(3):1299-1311.
[9]DENG L.Review of recent research progress in correlating HBV genotypes with efficacy of antiviral treatments[J].J Clin Hepatol,2012,28(6):469-473.(in Chinese)邓乐.乙型肝炎病毒基因型与抗病毒药物疗效关系的研究进展[J].临床肝胆病杂志,2012,28(6):469-473.
[10]BALACHANDRAN S,THOMAS E,BARBER GN.A FADD-dependent innate immune mechanism in mammalian cells[J].Nature,2004,432(7015):401-405.
[11]TAKAHASHI K,KAWAI T,KUMAR H,et al.Roles of caspase-8and caspase-10 in innate immune responses to double-stranded RNA[J].J Immunol,2006,176(8):4520-4524.
[12]BUSTER EH,HANSEN BE,LAU GK,et al.Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa[J].Gastroenterology,2009,137(6):2002-2009.
[13]SONNEVELD MJ,RIJCKBORST V,BOUCHER CA,et al.Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline[J].Hepatology,2010,52(4):1251-1257.
[14]TSENG TC,YU ML,LIU CJ,et al.Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-α-2a therapy[J].Antivir Ther,2011,16(5):629-637.
[15]HUANG YX,MA LN,CHEN XY,et al.Genetic polymorphisms of MxA protein and eIF-2a-reg2 and their responses to interferon treatment in patients with chronic hepatitis B[J].Chin J Hpeatol,2007,15(3):187-191.(in Chinese)黄雁翔,马丽娜,陈新月,等.粘病毒抵抗蛋白A和真核细胞起始因子2α调节区2基因多态性与慢性乙型肝炎干扰素治疗效果的相关性[J].中华肝脏病杂志,2007,15(3):187-191.
[16]WU X,ZHU X,ZHU S,et al.A pharmacogenetic study of polymorphisms in interferon pathway genes and response to interferonalpha treatment in chronic hepatitis B patients[J].Antiviral Res,2009,83(3):252-256.
[17]KING JK,YEH SH,LIN MW,et al.Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients:A pilot study[J].Hepatology,2002,36(6):1416-1424.
[18]LAMPERTICO P,VIGANOM,CHERONI C,et al.IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B[J].Hepatology,2013,57(3):890-896.
[19]SONNEVELD MJ,WONG VW,WOLTMAN AM,et al.Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B[J].Gastroenterology,2012,142(3):513-520.