Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Department of Gastroenterology, Peking University Third Hospital, Beijing, China.
J Hepatol. 2024 Jan;80(1):41-52. doi: 10.1016/j.jhep.2023.09.039. Epub 2023 Oct 18.
BACKGROUND & AIMS: HBsAg 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 functional cure of CHB can aid in identifying individuals who would benefit from peginterferon-α (Peg-IFNα) therapy.
We conducted a genome-wide association study (GWAS) by enrolling 48 patients with CHB who achieved HBsAg loss after Peg-IFNα treatment and 47 patients who didn't. In the validation stage, we included 224 patients, of whom 90 had achieved HBsAg loss, to validate the identified significant single nucleotide polymorphisms. To verify the functional involvement of the candidate genes identified, we performed a series of in vitro and in vivo experiments.
GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in patients with CHB after Peg-IFNα treatment (p = 4.85 × 10, odds ratio = 14.47). This association was also observed in two independent validation cohorts. Expression quantitative trait locus analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (p = 2.90 × 10). RNA-sequencing of liver biopsies from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 levels were significantly higher in the HBsAg loss group compared to the HBsAg persistence group (p = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated gene levels and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling.
The rs7519753 C allele is associated with elevated hepatic TP53BP2 expression and an increased probability of serum HBsAg loss post-Peg-IFNα treatment in patients with CHB. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression.
Chronic 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 rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in patients with CHB undergoing Peg-IFNα treatment. This finding not only provides a promising 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 based on their potential clinical implications.
只有一小部分接受干扰素治疗的慢性乙型肝炎（CHB）患者会出现 HBsAg 丢失。研究对 CHB 功能性治愈至关重要的宿主因素可以帮助确定哪些患者将从聚乙二醇干扰素-α（Peg-IFNα）治疗中获益。
我们通过招募 48 名接受 Peg-IFNα 治疗后 HBsAg 丢失的 CHB 患者和 47 名未丢失的患者进行全基因组关联研究（GWAS）。在验证阶段，我们纳入了 224 名患者，其中 90 名 HBsAg 丢失，以验证确定的显著单核苷酸多态性。为了验证候选基因的功能相关性，我们进行了一系列体外和体内实验。
GWAS 结果表明，rs7519753 C 等位基因与接受 Peg-IFNα 治疗后的 CHB 患者血清 HBsAg 丢失之间存在显著关联（p=4.85×10，优势比=14.47）。这一关联在两个独立的验证队列中也得到了观察。表达数量性状基因座分析显示，携带 rs7519753 C 等位基因的个体肝组织中 TP53BP2 表达水平较高（p=2.90×10）。接受 Peg-IFNα 治疗后的 CHB 患者肝活检的 RNA 测序显示，与 HBsAg 持续组相比，HBsAg 丢失组肝组织中 TP53BP2 水平显著升高（p=0.035）。体外和体内实验表明，TP53BP2 的缺失降低了干扰素刺激基因水平和 IFN-α 的抗乙型肝炎病毒作用。机制上，TP53BP2 被发现下调 SOCS2，从而促进 JAK/STAT 信号通路。
rs7519753 C 等位基因与接受 Peg-IFNα 治疗后的 CHB 患者肝组织中 TP53BP2 表达升高和血清 HBsAg 丢失的可能性增加相关。TP53BP2 通过抑制 SOCS2 的表达增强了肝细胞对 IFN-α 的反应。
慢性乙型肝炎（CHB）仍然是一个全球性的公共卫生问题。尽管目前的抗病毒疗法在阻止疾病进展方面更有效，但只有少数 CHB 患者能实现 HBsAg 丢失的功能性治愈，这突显了 CHB 急需治愈的紧迫性。本研究表明，与高肝组织 TP53BP2 表达相关的 rs7519753 C 等位基因，显著增加了接受 Peg-IFNα 治疗的 CHB 患者血清 HBsAg 丢失的可能性。这一发现不仅为 HBsAg 丢失提供了一个有希望的预测指标，还确定了 Peg-IFNα 治疗的一个潜在治疗靶点。我们相信，基于其潜在的临床意义，我们的研究结果将引起广泛利益相关者的极大兴趣。
