Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection

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.