IL-28B基因多态性-丙型肝炎个体化治疗的新起点

众所周知,个体基因的差异在慢性丙型肝炎患者的治疗中有重要的影响.2009-08/201001,世界上4个独立的全基因关联研究发现白介素28B的基因型与长效干扰素-利巴韦林的治疗效果相关联.同时证实,rs8099917和rs12979860的单核苷酸多肽性(single nucleotide polymorphisms,SNP)与抗病毒治疗的持续病毒应答率(sustained virological response,SVR)联系最为密切.本综述旨在阐述白介素28B多态性与丙型肝炎治疗效果、丙型肝炎病毒自发清除及分子流行病学特点、部分药物不良反应之间的联系.这些研究提示我们,在不久的将来,一个以白介素28B基因型为基础的个体化治疗时代将会来到.     

慢性丙型肝炎患者病毒基因型与IL-28B基因型分布

目的：了解慢性丙型肝炎患者白细胞介素-28B（IL-28B）基因型多态性分布的特点及其临床意义。方法在27例慢性丙型肝炎患者,分离外周血细胞DNA,采用IPLEX Gold法检测宿主IL-28B基因多态性;分析患者IL-28B基因型与血清丙型肝炎病毒（HCV）基因型、HCV RNA载量和肝功能指标的相关性。结果在27例慢性丙型肝炎患者中,感染HCV基因1型1例（3.7%）,1b基因型7例（25.9%）,其它基因型19例（19/27,70.4%）;在IL-28B基因型中,rs12979860 CC基因型、rs12980275 AA基因型及rs8099917 TT基因型共24例（88.9%）,而IL28B rs12979860 CT基因型、rs12980275 GA基因型和rs8099917 GT基因型共3例（11.1%）;在HCV基因1型或1b型感染者中,IL28B rs12979860 CC基因型、rs12980275 AA基因型和rs8099917 TT基因型占62.5%（5/8）,而HCV其他基因型感染者IL28B rs12979860 CC基因型、rs12980275 AA基因型和rs8099917 TT基因型占100%（19/19）;HCV基因1型或1b型感染者与HCV其他基因型感染者比,其IL28B rs12979860位点、rs12980275位点和rs8099917位点基因型分布有显著性差异（P＆lt;0.01）;IL-28B基因多态性分布与患者血清HCV RNA载量或肝功能指标的变化无显著性相关。结论本组慢性丙型肝炎患者HCV基因型大多为非1型;大多数感染者IL-28B基因为rs12979860 CC、rs12980275 AA和rs8099917 TT基因型。     

IL-28B基因多态性在丙型肝炎患者治疗中的作用

Interleukin(IL)-28B(interferon lambda 3,IFN-λ3)是一类属于IFN-λ家族的新型白介素,编码基因位于19号染色体上.近期的多项研究阐述了IL-28B的基因多态性(single nucleotide polymorphisms,SNPs)在丙型肝炎病毒(hepatitis C ...     

白细胞介素28B基因的单核苷酸多态性与HCV感染的治疗及预后

聚乙二醇干扰素α联合利巴韦林是目前治疗丙型肝炎普遍应用的方法.对于感染1型和4型基因型HCV的患者,40%治疗后获得持续病毒学应答(sustained virological response,SVR),而感染2型和3型基因型HCV的患者获得SVR率约为80%.非洲裔美国人(黑种人)1型基因型HCV感染者只有19%～28%在治疗后获得SVR,感染2型和3型基因型HCV的患者获得SVR率只有57%,比白种人和其他人种低.     

IL-28B基因多态性与丙型肝炎关系的研究进展

白细胞介素(interleukin,IL)-28B即干扰素λ3,是一类属于干扰素λ家族的新型IL,编码基因位于19号染色体上.IL-28B基因的单核苷酸多态性与基因1型HCV感染者自发清除以及聚乙二醇干扰素α和利巴韦林联合治疗抗病毒应答率之间的关系已有大量研究报道.然而,随着直接抗病毒药物的应用,IL-28B基因型对于三联疗法应答率的预测作用有待进一步研究.此外,IL-28B对基因2、3型HCV感染者抗病毒治疗应答率的影响尚不确定,对肝纤维化进展的影响也存在争议.本文就以上几方面的最新进展进行综述.     

IL-28B基因多态性与丙型肝炎易感性的关系

目的:探讨白介素-28B(interleukin-28B,IL-28B)单核苷酸多态性位点rs8099917与中国丙型肝炎易感性的关系.方法:采用TaqMan SNP基因分型的方法检测中国天津地区263名丙型肝炎患者和244名健康人IL-28B rs8099917基因型和等位基因分布情况,并统计分析rs8099917基因型和等位基因在2组中分布的差异.结果:在263名丙型肝炎患者中,TT基因型223人(84.8%),TG基因型39人(14.8%),GG基因型1人(0.4%).T等位基因频率为92.2%.244名健康对照者中,TT基因型222人(91.0%),TG21人(8.60%),GG1人(0.40%),T等位基因频率为95.3%.丙型肝炎患者和健康人群TG/GG基因型频率差异有统计学意义(OR=1.810,95%CI:1.042-3.145;P=0.033).丙型肝炎患者G等位基因频率也高于健康人(OR=1.709,95%CI:1.010-2.893;P=0.044).结论:中国人群IL-28B rs8099917基因多态性与丙型肝炎病毒(hepatitis C virus,HCV)感染易感性相关联.G为HCV感染的风险等位基因.     

慢性丙型肝炎患者IL-28B基因多态性检测及临床应用

目的 探讨慢性丙型肝炎患者IL-28B基因多态性的分布特征,进一步分析其与聚乙二醇干扰素（PEG—IFN-α）联合利巴韦林（RBV）治疗的关系。方法设计特异性引物和探针,建立连接酶检测反应体系,对42例接受治疗的慢性丙型肝炎患者IL-28B基因多态性进行检测。结果42例患者中,IL-28B基因区rs12979860基因型均为CC型（100％）;rs12980275基因型,AA型39例（92．9％）,AG型3例（7．1％）;rs8099917基因型,TT型39例（92．9％）,TG型3例（7．1％）。用药后快速应答34例,持续应答41例,患者均获得早期应答。结论IL-28B基因多态性在本地区存在特征分布,rs12979860基因型cc患者对PEG—IFN-a联合RBV治疗具有较高的应答率;IL-28B基因区rs12979860、rs8099917单核苷酸多态性检测对PEG—IFN-a联合RBV治疗效果的预测具有一定的意义。     

慢性丙型肝炎患者HCV基因型分析

目的研究慢性丙型肝炎患者HCV基因型概况。方法采用基因芯片法检测HCV基因分型;采用PCR法测定HCV RNA定量。结果在570例患者中,HCV RNA阳性552例（95%）,其中1b型400例（72.4%）,2a型63例（11.4%）,3a型20例（3.6%）,3b型20例（3.6%）,1b＋2a型12例（2.1%）,1a型2例（0.4%）,6型7例（1.26%）,1b＋3a型1例（0.18%）,2a＋1b型3例（0.5%）,未定型24例（4.3%）;不同HCV基因型感染者血清HCVRNA水平无统计学差异（P〉0.05）。结论本组患者HCV基因型以1b型为主,2a型次之,多种混合型的出现提示HCV基因型呈现多样化趋势。     

不同基因型慢性丙型肝炎患者血清HCV-RNA与载脂蛋白B的关系

目的研究慢性丙型肝炎基因1型和非基因1型患者血清HCV—RNA水平和血清载脂蛋白B（ApoB）的关系。方法临床确诊为慢性丙型肝炎的53例患者，采用干扰素联合利巴韦林抗病毒治疗至少24周，Simmonds酶切分型方法进行HCV基因分型，荧光定量聚合酶链反应法（FQ—PCR）定量检测HCV—RNA，全自动生化分析仪检测血清载脂蛋白B，对不同基因型患者血清HCV-RNA水平和载脂蛋白B的关系进行研究分析。结果基因1型和非基因1型慢性丙型肝炎患者的血清HCV-RNA及载脂蛋白B水平差异无统计学意义（P〉0．05）；基因1型患者血清载脂蛋白B水平与HCV—RNA载量无明显相关（P〉0．05）；非基因1型患者血清载脂蛋白B水平随着HCV-RNA载量的降低呈升高趋势（P〈0．05）。结论不同基因型HCV对干扰素产生不同的应答反应，感染HCV基因1型的患者对干扰素治疗应答率显著低于基因2型和3型。不同基因型HCV感染者血清载脂蛋白B无显著差异，血清ApoB水平在非基因1型患者与干扰素抗HCV应答密切相关。     

白细胞介素28B基因多态性与丙型肝炎治疗持续应答的关系

目的 探讨白细胞介素-28B(IL-28B)基因多态性与慢性丙型肝炎(CHC)患者抗病毒治疗持续应答的关系. 方法 220例CHC患者均接受聚乙二醇干扰素联合利巴韦林治疗48周,随访至停药后24周.检测IL-28B (rs8099917)位点,根据测序结果将HCV感染者分为TT组、GG组、GT组.探讨IL-28B单核苷酸多态性和CHC患者抗病毒持续应答的关系. 结果 220例CHC患者中,182例(82.7％)疗程结束时获得病毒学应答(ETVR),TT组和GT+GG组获得ETVR的比例分别是93.5％和68.8％,两者差异具有统计学意义(x2=23.287,P＜0.01);获得持续应答(SVR)的比例分别是86.2％和60.6％,两者差异具有统计学意义(x2 =15.531,P＜ 0.01).获得SVR患者中,TT组与GT+GG组的比值比(OR)为4.063,95％可信区间(CI)为1.972 ～ 8.369,x2=15.531,差异有统计学意义(P＜0.01);在复发患者中,TT组与GT+ GG组的OR为0.246 (95％CI:0.119 ～ 0.507),x2=15.531,差异有统计学意义(P＜0.01).结论 IL-28B (rs8099917)基因型与CHC患者抗病毒疗效密切,TT基因型患者较GT或GG型有更高的持续应答率及更低的复发率,可作为抗病毒疗效的一个重要预测因素.     

IL28B polymorphisms associated with therapy response in Chilean chronic hepatitis C patients

AIM:To analyze the association of three IL28B single nucleotide polymorphisms with response to therapy in Chilean patients infected with hepatitis C virus CV.METHODS:We studied two groups of patients with chronic CV infection genotype 1,under standard combined treatment with pegylated interferon plus ribavirin.One group consisted of 50 patients with sustained virological response,whereas the second group consisted of 49 null responders.In order to analyze the IL28B single nucleotide polymorphisms rs12979860...     

IL28B polymorphism as a predictor of antiviral response in chronic hepatitis C

AIM:To evaluate the effect of single nucleotide polymorphisms of interleukin(IL)-28B,rs12979860 on progression and treatment response in chronic hepatitis C.METHODS:Patients(n = 64;37 men,27 women;mean age,44 ± 12 years) with chronic hepatitis C,genotype 1,received treatment with peg-interferon plus ribavirin.Genotyping of rs12979860 was performed on peripheral blood DNA.Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment.Serum viral load,aminotransferase activity,and insulin level were measured.Insulin resistance index,body mass index,waist/hip ratio,percentage of body fat and fibrosis progression rate were calculated.Applied dose of interferon and ribavirin,platelet and neutrophil count and hemoglobin level were measured.RESULTS:A sustained virological response(SVR) was significantly associated with IL28B polymorphism(CC vs TT allele:odds ratio(OR),25;CC vs CT allele:OR,5.4),inflammation activity(G 1 vs G 1:OR,3.9),fibrosis(F 1 vs F 1:OR,5.9),platelet count( 200 × 10 9 /L vs 200 × 10 9 /L:OR,4.7;OR in patients with genotype CT:12.8),fatty liver(absence vs presence of steatosis:OR,4.8),insulin resistance index( 2.5 vs 2.5:OR,3.9),and baseline HCV viral load( 10 6 IU/mL vs 10 6 IU/mL:OR,3.0).There was no association with age,sex,aminotransferases activity,body mass index,waist/hip ratio,or percentage body fat.There was borderline significance(P = 0.064) of increased fibrosis in patients with the TT allele,and no differences in the insulin resistance index between groups of patients with CC,CT and TT alleles(P = 0.12).Spearman's rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605,respectively(P 0.001).Significant differences were found in the insulin resistance index(P = 0.01) between patients with and without steatosis.Patients with the CT allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon(P = 0.07).CONCLUSION:IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy.Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.     

IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4

Summary. Genetic polymorphisms near IL28B are associated with spontaneous and treatment‐induced clearance of hepatitis C virus (HCV). Our objective was to assess the predictive value of IL28B polymorphisms in the treatment of chronic hepatitis C of patients with HCV genotypes 4, for which data are currently limited. We analysed the association of IL28B polymorphisms with the virological response to treatment among 182 naïve chronic hepatitis C patients with HCV genotype 4, all from Syria. Associations of alleles with the response patterns were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. Sustained virological response (SVR) was achieved in 26% of rs8099917 TG/GG carriers compared with 60% of TT carriers (P < 0.0001) and 35% of rs12979860 CT/TT carriers compared with 62% of CC carriers (P = 0.0011). By multivariate analysis, the association between rs8099917 and SVR remained significant (OR = 0.19, 95% CI 0.07–0.50, for TG/GG vs TT, P = 0.0007), with the only significant covariate being advanced fibrosis (OR = 0.13, 95% CI 0.04–0.37, P = 0.0002). In conclusion, IL28B polymorphisms are the strongest predictors of response to therapy among chronic hepatitis C patients with HCV genotype 4.     

High sensitivity assay using serum sample for IL28B genotyping to predict treatment response in chronic hepatitis C patients

Aim: Recent human genome‐wide association studies (GWAS) revealed a strong association between IL28B gene variation and the pegylated interferon‐α with ribavirin (PEG‐IFN‐α/RBV) treatment response in chronic hepatitis C patients. Two single nucleotide polymorphisms (SNP), rs8103142 and rs11881222 located in the IL28B gene, were found in significant association with the viral clearance. The present study employed these SNPs to develop a new accessible screening method allowing identification of potential non‐responders before starting the therapy. Methods: Primer sets were designed to amplify rs8103142 and rs11881222 fragments from genomic DNA extracted from serum samples. This method was validated using microarray typing (GWAS) and applied for genotyping of 68 hepatitis C virus‐infected patients with PEG‐IFN‐α/RBV treatment at baseline. Results: In comparison with GWAS, the screening method showed 100% and 95.6% accuracy in typing of rs8103142 and rs11881222, respectively, indicating incomplete specificity but 100% of sensitivity in both. Genotyping by both SNP showed that 53 (77.9%), 14 (20.6%) and one (1.5%) of the patients were of major homozygous, heterozygous and minor homozygous type, respectively. The majority (85%) of homozygous patients exhibited response to therapy in contrast to heterozygous patients (29%). Among all genotyped only one case was found with the minor homozygous genotype which had late virological response to therapy before relapsing. Conclusion: This study described a highly sensitive assay that can be useful in determining SNP genotypes as well as in predicting the response to IFN‐based treatment.     

慢性丙型肝炎患者2型糖尿病并发率调查及其基因型特征分析

目的通过调查慢性丙型肝炎患者2型糖尿病并发率及其与所感染丙型肝炎病毒（HCV）基因型的关系。进一步探讨糖尿病是否为丙型肝炎的肝外表现之一。方法采用荧光定量聚合酶链反应和聚合酶链反应一微板核酸杂交酶联免疫技术对308例慢性丙型肝炎、305例慢性乙型肝炎患者进行乙型肝炎病毒、HCV定性．定量检测和HCV基因型分析并比较其与对照人群糖尿病并发率的差异。结果慢性丙型肝炎患者糖尿病并发率为32．79％，明显高于慢性乙型肝炎（9．84％）及对照组（8．39％）。合并糖尿病的慢性丙型肝炎患者血清丙氨酸氨基转移酶及总胆红素水平显著高于未合并糖尿病者，且以1b型HCV的感染率为最高，占40．59％，与未合并糖尿病者相比差异有统计学意义。结论慢性丙型肝炎患者糖尿病并发率高，以1b型多见，且病情相对较重。