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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.
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IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.

机译：IL28B基因型与慢性丙型肝炎患者肝内干扰素刺激基因的差异表达有关。

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摘要

Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-alpha and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells. Conclusion: The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.
机译：IL28B（白介素28B;干扰素λ3）区域的遗传变异与接受聚乙二醇干扰素-α和利巴韦林治疗的慢性丙型肝炎（CHC）患者的持续病毒学应答（SVR）率相关。我们假设IL28B多态性与干扰素刺激基因（ISG）的肝内表达有关，已知该基因会影响治疗效果。 IL28B基因分型（rs12979860）和全基因组RNA表达使用来自61名北美CHC患者的肝活检进行。经过多次测试校正（错误发现率<0.10）后，发现164个转录物被IL28B型差异表达。干扰素信号传导途径是IL28B型差异表达最丰富的经典途径（P <10（-5）），大多数基因在携带反应较差的IL28B型个体的肝脏中显示较高的表达。在可获得治疗反应数据的25例患者中，IL28B型与SVR相关（P = 0.0054）。 ISG表达也与SVR相关。但是，这并不独立于IL28B型。肝活检中miR-122表达的分析显示，与IL28B型无关，miR-122水平降低与较差的治疗结果相关。没有观察到IL28B类型与肝脏IL28B或IL28A信使RNA表达水平之间的关联。因此，在体外研究了与rs12979860相关的IL28B蛋白序列变异体：在Huh7.5细胞中未观察到ISG诱导或HCV复制抑制的差异。结论：应答良好的IL28B变体与较低水平的ISG表达密切相关。结果表明IL28B基因型可以解释肝脏ISG表达与HCV治疗结果之间的关系，而这与miR-122表达无关。 IL28B型与体内肝内IL28B信使RNA表达无关。有必要进一步研究IL28B遗传变异影响HCV结果的精确分子机制。

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