An HBV susceptibility variant of KNG1 modulates the therapeutic effects of interferons & alpha; and 11 in HBV infection by promoting MAVS lysosomal degradation

Background 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.Methods 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-& alpha;/11.Findings 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-& alpha; and -11 in HBV infection.Interpretation 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.

Automated summary

By performing whole-genome exon sequencing analysis on 300 Chinese HBV-infected families, this study identified variants and genes associated with HBV infection. The rs76438938 SNP in the KNG1 gene was found to significantly increase the risk for HBV infection and promote HBV replication. Additionally, KNG1 was shown to inhibit the expression of type I and III interferons by competitively binding HSP90A with MAVS, thereby further promoting HBV replication. Furthermore, the rs76438938-C allele was found to improve the therapeutic effect of IFN-α and -11 in HBV infection.