Persistent Effect of IFNAR-1 Genetic Polymorphism on the Long-Term Pathogenesis of Chronic HBV Infection

Abstract

Genetic polymorphism of IFNAR-1 plays a large role in determining the clearance or chronicity after hepatitis B virus (HBV) exposure. However, it is not clear whether type I interferon receptor-1 (IFNAR-1) variations continuously exert their effects to influence the final outcomes following HBV chronicity, including acute-on-chronic hepatitis B liver failure (ACLF-HBV), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here we report that these four potential outcomes of chronic HBV infection are strongly associated with IFNAR-1 polymorphisms through a hospital-based case-control study of 663 cases. ACLF-HBV and HCC were each compared with CHB+LC. In comparison with the G/G genotype, the C/G and C/C genotypes at both single-nucleotide polymorphism (SNP) sites (rs1012335 and rs2257167) showed significant susceptibility to ACLF-HBV (the highest odds ratio [OR] reached 2.374; 95% CI = 1.488, 3.788; p < 0.001 for the C/G genotype at rs2257167), as well as HCC (OR = 2.475; 95% CI = 1.435, 4.426; p < 0.001 for the C/C genotype at rs1012335). The C allele at both loci was a susceptibility allele for ACLF-HBV and HCC, with the highest ORs reaching 1.653 (95% CI = 1.233, 2.216; p < 0.01 at rs1012335) in the ACLF-HBV group, and 1.659 (95% CI = 1.274, 2.159; p < 0.01 at rs1012335) in the HCC group. A strongly linked disequilibrium was also found within these two alleles (p < 0.001). Our research indicates that genetic polymorphisms of IFNAR-1 not only contribute to the determination of clearance or chronicity in the early stages of HBV exposure, but they also persistently influence pathogenesis over the long-term process of chronic HBV infection.

Hepatitis B Virus Nucleocapsid but Not Free Core Antigen Controls Viral Clearance in Mice

“…Both type I and II IFNs, as well as proinflammatory cytokines such as interleukin-6, are induced in response to HBV infection. Moreover, deficiencies in the innate immunity tampered with the control of HBV infection (10,12,37,38). Using hydrodynamics-based transfection in a series of knockout mice, Yang et al demonstrated the involvement of innate immunity-related effectors in the HBV clearance, including IFN-␣/␤ receptor 1, IFN-␥, and tumor necrosis factor (TNF) receptor 1 (35).…”

Matrix Metalloproteinase 9 Facilitates Hepatitis B Virus Replication through Binding with Type I Interferon (IFN) Receptor 1 To Repress IFN/JAK/STAT Signaling

“…It was reported previously that a lower level of IFNAR1 is associated with a higher risk of liver diseases (54), and polymorphisms of the IFNAR1 promoter are associated with CHB and HCC susceptibility (55,56). IFNAR1 is downregulated by HBx in hepatocytes and in woodchucks infected with WHV (57, 58), indicating that HBV/WHV may establish chronic infection by repressing IFNAR1.…”

Association between the <b><i>IFNA1 </i></b>(-2C&#x2192;T) Polymorphism and Increased <b><i>IFNAR1 </i></b>Gene Expression Levels in Chronic Hepatitis B Infection

“…In addition to the identification of SNPs, IFN-γ and IFN-α cytokine expression patterns and genetic variations in the IFN-α receptor subunit 1 (IFN-α r1) might affect clearance rates or contribute to the development of chronicity of early-stage HBV. It may also persistently influence HBV pathogenesis during the chronic long-term infectious process [13]. …”

“…Furthermore, several studies found that IFNAR1 gene polymorphisms in promoter, intron and exon regions were associated with HBV infection [13,17,18]. However, data on genes polymorphisms in IFNG (-5A→G), IFNA1 (-2C→T) and IFNAR1 (-97T→C) regions are lacking.…”