Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
PLoS Med. 2011 Sep;8(9):e1001092. doi: 10.1371/journal.pmed.1001092. Epub 2011 Sep 13.
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10(-8), 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10(-14), 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10(-6), 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
迄今为止，药物反应基因在临床实践中的应用并没有像基因组时代开始时预期的那样有用。慢性丙型肝炎病毒（HCV）基因型 1 感染的聚乙二醇干扰素-α和利巴韦林（PegIFN/R）治疗是一个例外。该治疗方案能使 40%-50%的患者清除病毒。白细胞介素 28B（IL28B）基因型可预测治疗诱导和自发性清除。为了提高该基因型的预测价值，我们研究了 IL28B 变体与人类白细胞抗原 C（HLA-C）及其配体杀伤免疫球蛋白样受体（KIR）的联合效应，这些受体先前与 HCV 病毒控制有关。
我们对接受 PegIFN/R 治疗诱导清除（n=417）和治疗失败（n=493）的慢性丙型肝炎（CHC）基因型 1 患者以及 234 例自发性清除患者进行了 IL28B 基因分型，检测 HLA-C C1 与 C2、抑制性和激活性 KIR 基因以及两个 IL28B SNPs（rs8099917 和 rs12979860）。所有患者均为欧洲人或欧洲裔。IL28B SNP rs8099917“G”与治疗诱导清除失败（比值比[OR]2.19，p=1.27×10（-8），1.67-2.88）和 HCV 自发性清除失败（OR 3.83，p=1.71×10（-14），2.67-5.48）相关，rs12979860 也具有略低的 OR。HLA-C C2C2 基因型在治疗失败的患者中也更为常见（OR 1.52，p=0.024，1.05-2.20），但与自发性清除无关。在该队列中，使用这两个基因可将治疗失败的预测从 IL28B 的 66%提高到 80%（OR 3.78，p=8.83×10（-6），2.03-7.04）。有证据表明，KIR2DL3 和 KIR2DS2 携带也改变了与 HLA-C 和 IL28B 联合的 HCV 治疗反应。
IL28B、HLA-C 和 KIR 基因的基因分型可提高对 HCV 治疗反应的预测。这些发现支持自然杀伤（NK）细胞激活在 PegIFN/R 治疗诱导清除中的作用，部分由 IL28B 介导。
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