CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports Pub Date : 2024-03-08 DOI:10.1016/j.jhepr.2024.101061

Jia-Feng Wu , Chi-San Tai , Kai-Chi Chang , Ting-Wei Chen , Huey-Ling Chen , Yen-Hsuan Ni , Hong-Yuan Hsu , Mei-Hwei Chang

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Abstract

Background & Aim

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection.

Methods

We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (–A1661G)/rs5742909 (–C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort.

Results

CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log₁₀ IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01).

Conclusions

Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion.

Impact and implications

The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.

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CTLA-4 单倍型可预测慢性 HBV 感染儿童的 HBsAg 和 HBcrAg 水平以及 HBeAg 血清转换年龄

背景& 目的细胞毒性T淋巴细胞相关蛋白4（CTLA-4）可减轻细胞毒性T淋巴细胞（CTL）的活化。本研究旨在探讨 CTLA-4 基因型/单倍型与乙型肝炎表面抗原（HBsAg）和乙型肝炎核心相关抗原（HBcrAg）水平之间的关系及其对慢性 HBV 感染临床过程的潜在影响。方法我们招募了 145 名基因 B 型或 C 型慢性 HBV 感染的未经治疗的患者，他们最初的乙肝 e 抗原（HBeAg）呈阳性，并从平均年龄 7.08 岁开始接受随访，研究队列中的患者总计达 4,787 人年。我们还招募了另外 69 名基因 B 型或 C 型慢性 HBV 感染的治疗无效成人作为验证队列。我们对两个队列中的 CTLA-4 基因单核苷酸多态性 rs4553808 (-A1661G)/rs5742909 (-C318T) 以及研究队列中的血清 HBsAg 和 HBcrAg 水平进行了评估。与其他患者相比，CTLA-4 AA/CC 单倍型患者表现出更早的自发 HBeAg 血清转换（危险比 = 1.58；p = 0.02），血清 HBsAg 水平的年下降速度更快（0.09 对 0.03 log10 IU/ml/年，p = 0.02）。结论具有 CTLA-4 AA/CC 单倍型的慢性 HBV 感染者在儿童期的血清 HBsAg 和 HBcrAg 水平较低，自发 HBeAg 血清转换较早。影响和意义此前尚未研究过细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 在慢性 HBV 感染儿童中的作用。在一个从儿童到成年的长期队列中，我们发现 CTLA-4 单倍型与儿童期的 HBV 生物标志物水平相关，并与慢性 HBV 感染的临床过程相关。CTLA-4 通路可能是未来开发 HBV 感染治疗药物的靶点。

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来源期刊

JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

12.40

自引率

2.40%

发文量

161

审稿时长

36 days

期刊介绍： JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.