Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.
J Transl Med. 2012 Feb 7;10:25. doi: 10.1186/1479-5876-10-25.
Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.
Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
最近对 CH-C 患者的研究表明，IL28B CC 基因型与 PEG-IFN/RBV 治疗后的持续病毒学应答（SVR）之间存在很强的关联。我们旨在评估 IL28B 等位基因 rs12979860 基因型是否影响 CH-C 患者对 PEG-IFN/RBV 的基因表达。
为 56 名接受 PEG-IFN/RBV 治疗的患者提供了临床数据和基因表达数据。使用全血确定 IL28B 基因型。评估了每个治疗时间点（天：0、1、7、28、56）的 153 个人类基因的差异表达，并在 PEG-IFN/RBV 治疗过程中与 IL28B 基因型（IL28B C/C 或非-C/C）相关联。在每个时间点表达发生统计学显着变化的基因被用作 KEGG 途径绘图器（KPP）的通路分析的输入。根据每个研究队列中涉及的基因数量，对途径进行了排序。
在治疗过程中，IL28B C/C 和 T基因型患者的反应模式之间最显着的差异是，携带 IL28B C/C 的患者中存在持续的治疗诱导基因表达模式。在 IL28B T基因型的情况下，观察到基因的预激活、缺乏持续的基因表达模式或两者的组合。这种观察结果可能为这些患者中观察到的 SVR 率较低提供了解释。此外，当比较未达到 SVR 的患者的基线时，IL28B 基因型特异性差异表达基因的列表时，IRF2 和 SOCS1 基因无论患者的 IL28B 基因型如何均下调。此外，我们的数据表明，未沉默 SOCS1 基因的 CH-C 患者更有可能实现 SVR。我们的观察表明，SOCS1 的作用独立于 IL28B 基因型。
CH-C 患者的 IL28B CC 基因型表现出持续的治疗诱导基因表达谱，而非 CC 基因型患者则未见。SOCS1 的沉默是 SVR 的负面且独立的预测因子。这些数据可能为 PEG-IFN/RBV 治疗的 IL28B CC 患者 SVR 率较高提供一些机制解释。
