State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Vanderbilt University School of Medicine, Nashville, TN, USA.
EBioMedicine. 2023 Aug;94:104694. doi: 10.1016/j.ebiom.2023.104694. Epub 2023 Jul 11.
Hepatitis B virus (HBV) infection is one of the main causes of hepatocellular carcinoma (HCC). The relationship between HBV infection and the host genome as well as their underlying mechanisms remain largely unknown.
In this study, we performed a whole-genome exon sequencing analysis of 300 sib-pairs of Chinese HBV-infected families with the goal of identifying variants and genes involved in HBV infection. A site-direct mutant plasmid was used to investigate the function of SNP rs76438938 in KNG1. The functional and mechanical studies of KNG1 were conducted with in vitro liver cell lines and a hydrodynamic injection model in vivo. The impact of KNG1 on HBV infection therapy was determined in hepatocytes treated with IFN-α/λ1.
Our whole-exon association study of 300 families with hepatitis B infection found that SNP rs76438938 in KNG1 significantly increased the risk for HBV infection, and the rs76438938-T allele was found to promote HBV replication by increasing the stability of KNG1 mRNA. By competitively binding HSP90A with MAVS, KNG1 can inhibit the expression of types I and III IFNs by promoting MAVS lysosomal degradation. Such suppression of IFN expression and promotion of HBV replication by Kng1 were further demonstrated with an animal model in vivo. Lastly, we showed that the rs76438938-C allele can improve the therapeutic effect of IFN-α and -λ1 in HBV infection.
This study identified a SNP, rs76438938, in a newly discovered host gene, KNG1, for its involvement in HBV infection and treatment effect through modulating the cellular antiviral process.
This study was supported in part by the Independent Task of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases of the First Affiliated Hospital of Zhejiang University, the China Precision Medicine Initiative (2016YFC0906300), and the Research Center for Air Pollution and Health of Zhejiang University.
乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要病因之一。HBV 感染与宿主基因组之间的关系及其潜在机制在很大程度上仍不清楚。
本研究对 300 对中国 HBV 感染家系的兄弟姐妹进行了全基因组外显子测序分析，旨在鉴定与 HBV 感染相关的变异和基因。使用定点突变质粒研究 SNP rs76438938 在 KNG1 中的作用。通过体外肝细胞系和体内水力注射模型进行 KNG1 的功能和机械研究。在接受 IFN-α/λ1 治疗的肝细胞中，确定 KNG1 对 HBV 感染治疗的影响。
我们对 300 个乙型肝炎感染家族的全外显子关联研究发现，KNG1 中的 SNP rs76438938 显著增加了 HBV 感染的风险，并且 rs76438938-T 等位基因通过增加 KNG1 mRNA 的稳定性，促进 HBV 复制。通过与 MAVS 竞争结合 HSP90A，KNG1 可以通过促进 MAVS 溶酶体降解来抑制 I 型和 III 型 IFNs 的表达。在体内动物模型中进一步证实了 Kng1 对 IFN 表达的抑制和 HBV 复制的促进作用。最后，我们表明 rs76438938-C 等位基因可以改善 HBV 感染中 IFN-α 和 -λ1 的治疗效果。
本研究通过调节细胞抗病毒过程，在一个新发现的宿主基因 KNG1 中发现了一个 SNP rs76438938，该 SNP 参与了 HBV 感染和治疗效果。
本研究得到了浙江大学第一附属医院传染病诊治国家重点实验室自主任务、中国精准医学倡议（2016YFC0906300）和浙江大学空气污染与健康研究中心的支持。
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