Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B

Background & AimsHBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for CHB functional cure can aid in identifying individuals who would benefit from Peginterferon-alpha (Peg-IFNα) therapy.MethodsWe conducted a Genome-wide association study (GWAS) by enrolling 48 CHB patients with HBsAg loss and 47 with HBsAg persistence after Peg-IFNα treatment. In the validation stage, we included a total of 224 samples, out of which 90 achieved HBsAg loss, to validate the identified significant SNPs. To verify the functional involvement of candidate genes identified, we performed a series of in vitro and in vivo experiments.ResultsGWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in CHB patients after Peg-IFNα treatment (P = 4.85 × 10-8, OR = 14.47). This association was also observed in two independent validation cohorts. eQTL analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (P = 2.90 × 10-6). Liver biopsy RNA-seq from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 level in the HBsAg loss group was significantly higher compared to the HBsAg persistence group (P = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated genes (ISGs) level and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling.ConclusionRs7519753 C allele is associated with an increased probability of serum HBsAg loss in patients with CHB post-Peg-IFNα treatment and elevated hepatic TP53BP2 expression. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression.Impact and implicationsChronic Hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the SNP rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in CHB patients undergoing Peg-IFNα therapy. This finding not only provides an exciting predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders, including patients and patient organizations, the medical community, academia, the life science industry, and the general public.