Abstract
TP53BP2 IS ASSOCIATED WITH HBsAg CLEARANCE IN PEGINTERFERON-ALFA-TREATED CHRONIC HEPATITIS B
Background: Hepatitis B surface Antigen (HBsAg) loss occurs in a minor fraction of patients with Chronic Hepatitis B (CHB) under interferon therapy. Identifying the host factors critical for CHB cure can help recognize those who would benefit from interferon therapy.
Methods: This study enrolled a total of 95 CHB patients, 48 achieved HBsAg loss under Peginterferon-alpha (Peg-IFNα) therapy while 47 did not. A Genome-Wide Association Study (GWAS) was conducted on these patients to pinpoint the host gene(s) contributing to HBsAg loss. We then validated the results in an additional cohort of 207 patients, 81 of whom achieved HBsAg loss. Expression Quantitative Trait Loci (eQTL) analyses, RNAseq analysis of liver biopsies from interferon-treated patients, and a series of in vivo and in vitro experiments using interferon treatment were then used to verify the functional involvement of the identified candidate gene.
Results: The Single Nucleotide Polymorphism (SNP) rs7519753-C allele was found significantly associated with serum HBsAg loss in CHB patients undergoing Peg-IFNα treatment (P = 4.85 * 10-8, OR = 14.47). This association was consistently observed in the validation cohort, where the frequency of rs7519753-C genotype was significantly higher in the HBsAg loss group (P = 0.008312, OR =1.64). RNA-seq analysis of liver biopsies from interferon-treated patients showed that the expression of TP53BP2 was significantly higher in the HBsAg loss group (p < 0.05). The population carrying the rs7519753 C allele had higher TP53BP2 expression in the liver (P = 2.9 * 10-6). Additional experiments demonstrated that TP53BP2 amplified the expression of Interferon-Stimulated Genes (ISGs) in the presence of interferon. Mechanistically, TP53BP2 could post-transcriptionally downregulate the expression of SOCS2, thus enhancing the antiviral activity of the JAK/STAT signaling pathway activated by interferon therapy.
Conclusion: The SNP rs7519753-C allele correlates with a higher probability of serum HBsAg loss in CHB patients undergoing Peg-IFNα treatment and higher hepatic TP53BP2 expression. TP53BP2 can potentiate the hepatocyte response to IFN-α by inhibiting SOCS family gene expression. This suggests a pivotal role of TP53BP2 in predicting and enhancing interferon response in CHB patients.