Unraveling the Causal Links between Immune Traits and Hepatocellular Carcinoma: Insights From a Bi-Directional Mendelian Randomization Study

<b>Abstract</b><b>Background/Aims</b>: 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.<b>Materials and Methods</b>: Genome-wide association study (GWAS) summary statistics from the FinnGen cohort (R9, including 453 HCC cases and 287,137 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, was used to ensure the robustness and validity of the results.<b>Results</b>: We identified 39 immune traits significantly associated with HCC risk. Elevated levels of 10 immune traits were positively associated with increased HCC risk, while abundance of 29 immune traits were inversely correlated with HCC incidence. Furthermore, our reverse MR analysis revealed significant causal effects of HCC on 11 immune traits.<b>Conclusion</b>: 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.

**摘要**
**背景与目的**：肝细胞癌（Hepatocellular carcinoma, HCC）的发生、进展、治疗及预后均受免疫系统显著影响，免疫系统在其中发挥关键调控作用。既往观察性研究已揭示循环免疫特征与肝细胞癌之间存在相关性，但其遗传基础及因果关联仍不明确。本研究旨在采用孟德尔随机化（Mendelian randomization, MR）方法，探究免疫特征与肝细胞癌风险之间的遗传关联及双向因果关系。
**材料与方法**：本研究使用芬兰基因（FinnGen）队列（R9版本，包含453例肝细胞癌患者与287137例对照）的全基因组关联研究（Genome-wide association study, GWAS）汇总统计数据，开展双向两样本孟德尔随机化分析，以评估免疫特征对肝细胞癌的因果效应，以及肝细胞癌对免疫特征的反向因果效应。同时通过异质性检验、多效性检验等敏感性分析，确保研究结果的稳健性与有效性。
**结果**：本研究共鉴定出39种与肝细胞癌风险显著相关的免疫特征。其中10种免疫特征水平升高与肝细胞癌风险增加呈正相关，而29种免疫特征的丰度与肝细胞癌发病率呈负相关。此外，反向孟德尔随机化分析显示，肝细胞癌对11种免疫特征存在显著因果效应。
**结论**：本研究为系统性免疫细胞谱与肝细胞癌之间的遗传关联提供了坚实证据，为阐明肝细胞癌的发病与进展机制提供了新视角。本研究发现可为肝细胞癌早期诊断的潜在免疫生物标志物及免疫靶向治疗提供理论依据。