Li Jie, Wang Gechun, Xiang Xiaonan, Wang Jiaguo
Department of Hepatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
Department of Ophthalmology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.
Turk J Gastroenterol. 2025 Apr 21;36(7):420-30. doi: 10.5152/tjg.2025.24558.
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is significantly influenced by the immune system, which plays a key role in its development, progression, treatment, and prognosis. While observational studies have revealed correlations between circulating immune traits and HCC, their genetic basis and causal links remain unclear. This study aims to investigate the genetic associations and bidirectional causal relationships between immune traits and HCC risk using Mendelian randomization (MR) approaches.
Genome-wide association study summary statistics from the FinnGen cohort (R9, including 453 HCC cases and 287137 controls) were used to perform a bidirectional two-sample MR analysis. The causal effects of immune traits on HCC, as well as reverse causality, were assessed. Sensitivity analyses, including heterogeneity and pleiotropy tests, were used to ensure the robustness and validity of the results.
Thirty-nine immune traits were identified to be significantly associated with HCC risk. Elevated levels of 10 immune traits were positively associated with increased HCC risk, while the abundance of 29 immune traits was inversely correlated with HCC incidence. Furthermore, the reverse MR analysis revealed significant causal effects of HCC on 11 immune traits.
This study provides strong evidence of genetic links between systematic immune cell profiles and HCC, shedding light on the mechanisms underlying its onset and progression. These findings identify potential immune biomarkers for early diagnosis and immune-targeted therapies.
背景/目的：肝细胞癌（HCC）受免疫系统的显著影响，免疫系统在其发生、发展、治疗及预后中起关键作用。尽管观察性研究已揭示循环免疫特征与HCC之间的相关性，但其遗传基础和因果关系仍不明确。本研究旨在使用孟德尔随机化（MR）方法探究免疫特征与HCC风险之间的遗传关联及双向因果关系。
利用芬兰基因组队列（R9，包括453例HCC病例和287137例对照）的全基因组关联研究汇总统计数据进行双向双样本MR分析。评估免疫特征对HCC的因果效应以及反向因果关系。采用敏感性分析，包括异质性和多效性检验，以确保结果的稳健性和有效性。
确定39种免疫特征与HCC风险显著相关。10种免疫特征水平升高与HCC风险增加呈正相关，而29种免疫特征的丰度与HCC发病率呈负相关。此外，反向MR分析揭示了HCC对11种免疫特征有显著的因果效应。
本研究为系统性免疫细胞谱与HCC之间的遗传联系提供了有力证据，阐明了其发病和进展的潜在机制。这些发现确定了用于早期诊断和免疫靶向治疗的潜在免疫生物标志物。
