IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.
IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.
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DOI：
10.1002/hep.23912
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发表时间：
2010-12
期刊：
影响因子：
13.5
通讯作者：
Afdhal, Nezam
中科院分区：
文献类型：
--
作者：
Urban, Thomas J.;Thompson, Alexander J.;Bradrick, Shelton S.;Fellay, Jacques;Schuppan, Detlef;Cronin, Kenneth D.;Hong, Linda;McKenzie, Alexander;Patel, Keyur;Shianna, Kevin V.;McHutchison, John G.;Goldstein, David B.;Afdhal, Nezam
IL 28 B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IL 28 B多态性与干扰素刺激基因（ISG）的肝内表达相关，已知ISG影响治疗结果。IL 28 B基因分型（rs 12979860）和全基因组RNA表达使用61例北美CHC患者的肝活检进行。经多重检验校正后（错误发现率< 0.10），发现164个转录本与IL 28 B型差异表达。干扰素信号通路是IL 28 B型差异表达最丰富的经典通路（p < 10−5），大多数基因在携带低反应IL 28 B型个体的肝脏中显示出更高的表达。在25例治疗反应数据可用的患者中，IL 28 B型与SVR相关（p = 0.0054）。ISG表达也与SVR相关;然而，这并不独立于IL 28 B型。对肝活检组织中miR-122表达的分析显示，miR-122水平降低与较差的治疗结果相关，与IL 28 B类型无关。未观察到IL 28 B类型与肝脏IL 28 B或IL 28 A mRNA表达水平之间的相关性。因此，在体外研究了与rs 12979860相关的IL 28 B蛋白序列变体：在Huh7.5细胞中未观察到ISG诱导或抑制HCV复制的差异。良好反应的IL 28 B变体与较低水平的ISG表达强烈相关。结果表明，IL 28 B基因型可以解释肝脏ISG表达与HCV治疗结果之间的关系，并且这与miR-122表达无关。IL 28 B型与肝内IL 28 B mRNA表达无相关性。需要进一步研究IL 28 B基因变异影响HCV结局的确切分子机制。
Genetic variation in the IL28B region has been associated with sustained virological response (SVR) rates in chronic hepatitis C (CHC) patients treated with peginterferon-α 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 CHC patients. 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 mRNA 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. 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 mRNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.
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