A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection
A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection
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DOI：
10.1073/pnas.0609954104
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发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
Liang, T. Jake
中科院分区：
文献类型：
--
作者：
Huang, Ying;Yang, Huiying;Liang, T. Jake
细胞因子多态性与丙型肝炎病毒（HCV）感染的疾病结局和干扰素（IFN）治疗反应相关。我们在两个队列中对跨越整个ifn - γ基因的8个snp进行了基因分型，并评估了这些多态性与治疗反应或自发病毒清除之间的关系。第一组由284名接受ifn - α治疗的慢性HCV感染患者组成，第二组由251名静脉吸毒者组成，他们要么自发清除HCV，要么成为慢性感染。在热休克转录因子（HSF）结合基序-764G附近ifn - γ启动子区域的一个SNP变异与持续病毒学应答显著相关[P = 0.04，优势比(OR) = 3.51（置信区间1.0-12.5）]。在多元逻辑回归中，该相关性与种族、病毒滴度和基因型具有独立显著性（P = 0.04）。在第二队列中，该变异也与自发恢复显著相关[P = 0.04, OR = 3.51(1.0-12.5)]。功能分析表明，G等位基因的启动子活性比C等位基因高2 - 3倍，与HSF1的结合亲和力更强。我们的研究表明，ifn - γ启动子SNP -764G/C在确定hcv感染患者的病毒清除和治疗反应方面具有重要的功能，并且可以用作预测hcv感染患者持续病毒学反应的遗传标记。
Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-alpha-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-gamma promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.