Duke Clinical Research Institute, Duke University, Durham, NC 27715, USA.
Hepatology. 2011 Jun;53(6):1809-18. doi: 10.1002/hep.24284. Epub 2011 May 14.
Chronic hepatitis C (CHC) infection is a leading cause of endstage liver disease. Current standard-of-care (SOC) interferon-based therapy results in sustained virological response (SVR) in only one-half of patients, and is associated with significant side effects. Accurate host predictors of virologic response are needed to individualize treatment regimens. We applied a label-free liquid chromatography mass spectrometry (LC-MS)-based proteomics discovery platform to pretreatment sera from a well-characterized and matched training cohort of 55 CHC patients, and an independent validation set of 41 CHC genotype 1 patients with characterized IL28B genotype. Accurate mass and retention time methods aligned samples to generate quantitative peptide data, with predictive modeling using Bayesian sparse latent factor regression. We identified 105 proteins of interest with two or more peptides, and a total of 3,768 peptides. Regression modeling selected three identified metaproteins, vitamin D binding protein, alpha 2 HS glycoprotein, and Complement C5, with a high predictive area under the receiver operator characteristic curve (AUROC) of 0.90 for SVR in the training cohort. A model averaging approach for identified peptides resulted in an AUROC of 0.86 in the validation cohort, and correctly identified virologic response in 71% of patients without the favorable IL28B "responder" genotype.
Our preliminary data indicate that a serum-based protein signature can accurately predict treatment response to current SOC in most CHC patients.
慢性丙型肝炎（CHC）感染是终末期肝病的主要原因。目前的标准护理（SOC）基于干扰素的治疗方法仅使一半的患者获得持续病毒学应答（SVR），并且与明显的副作用相关。需要准确的宿主病毒学反应预测因子来个体化治疗方案。我们应用了无标签的液相色谱-质谱（LC-MS）基于蛋白质组学的发现平台，对来自 55 名经过充分特征描述和匹配的 CHC 患者训练队列以及具有特征性 IL28B 基因型的 41 名 CHC 基因型 1 患者的独立验证队列的预处理血清进行了分析。精确质量和保留时间方法将样品对齐以生成定量肽数据，并用贝叶斯稀疏潜在因子回归进行预测建模。我们鉴定了 105 种具有两个或更多肽的感兴趣蛋白，总共鉴定了 3768 个肽。回归建模选择了三种已识别的代谢蛋白，即维生素 D 结合蛋白，α 2 HS 糖蛋白和补体 C5，其在训练队列中的 SVR 预测性面积下的接收者操作特征曲线（AUROC）为 0.90。对于鉴定的肽，模型平均方法在验证队列中的 AUROC 为 0.86，并且在没有有利的 IL28B“应答者”基因型的情况下，正确识别了 71％的患者的病毒学反应。
我们的初步数据表明，基于血清的蛋白质特征可以准确预测大多数 CHC 患者对当前 SOC 的治疗反应。
