A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.
A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.
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DOI：
10.1038/ng.2521
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发表时间：
2013-02
期刊：
影响因子：
30.8
通讯作者：
O'Brien, Thomas R.
中科院分区：
文献类型：
--
作者：
Prokunina-Olsson, Ludmila;Muchmore, Brian;Tang, Wei;Pfeiffer, Ruth M.;Park, Heiyoung;Dickensheets, Harold;Hergott, Dianna;Porter-Gill, Patricia;Mumy, Adam;Kohaar, Indu;Chen, Sabrina;Brand, Nathan;Tarway, McAnthony;Liu, Luyang;Sheikh, Faruk;Astemborski, Jacquie;Bonkovsky, Herbert L.;Edlin, Brian R.;Howell, Charles D.;Morgan, Timothy R.;Thomas, David L.;Rehermann, Barbara;Donnelly, Raymond P.;O'Brien, Thomas R.
慢性感染丙型肝炎病毒(丙型肝炎病毒)是导致肝硬化和癌症的常见原因。我们在用合成dsRNA激活的原代人肝细胞中进行了RNA测序，以模拟丙型肝炎病毒感染。在19q13.13号染色体上IFNL3(IL28B)的上游，我们发现了一个新的瞬时诱导区，该区域含有二核苷酸变体ss469415590(TT/ΔG)，它与与丙型肝炎病毒清除密切相关的遗传标记rs12979860处于高度连锁不平衡状态。SS469415590-ΔG是一种移码变异体，它产生了一种新的灵长类特异基因，命名为干扰素lambda 4(IFNL4)，它编码的蛋白质与IFNL3具有中等的相似性。与rs12979860相比，在非洲血统的个体中，ss469415590与丙型肝炎病毒清除的相关性更强，而它在欧洲人和亚洲人中提供了类似的信息。肝癌细胞系瞬时过表达IFNL4诱导STAT1/STAT2磷酸化和干扰素刺激基因表达我们的发现为丙型肝炎病毒清除的基因调控及其临床管理提供了新的见解。
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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