Liu Jia, Zhang Tongyuan, Gao Yang, Ji Dong, Chen Lijian
Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
BMC Cancer. 2025 May 23;25(1):928. doi: 10.1186/s12885-025-14327-1.
Primary liver cancer is one of the most common fatal malignancies worldwide. Observational studies have shown that immune cells are closely linked to primary liver cancer, however, due to issues like reverse causality and confounding variables, the causal direction and extent of this association remain unclear. Thus, this study aimed to explore the potential causal association between immune cells and primary liver cancer, encompassing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).
A two-sample mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWAS) of the 731 immune traits and primary liver cancer. The primary liver cancer dataset consisted of a total of 456,348 subjects, with 123 cases of HCC and 456,225 controls, as well as 104 cases of ICC and 456,244 controls, all of European ancestry. The primary method for assessing causality was inverse variance weighting (IVW), with sensitivity analysis utilized for testing heterogeneity and pleiotropy.
Two immunophenotypes were significantly associated with HCC risk: CD3 on CD45RA + CD4+ (OR [95% CI]: 1.334 [1.077 to 1.651], p = 0.008), CD80 on monocyte (OR [95% CI]: 0.578 [0.397 to 0.844], p = 0.004). Additionally, six immunophenotypes were identified to be significantly associated with the risk of ICC: SSC-A on NK (OR [95% CI]: 1.685 [1.166 to 2.436], p = 0.006); CD3 on CD28- CD8br: (OR [95% CI]: 1.826 [1.206 to 2.766], p = 0.004); CD45RA on naive CD4+: (OR [95% CI]: 1.391 [1.119 to 1.729], p = 0.003); Resting Treg %CD4: (OR [95% CI]: 1.290 [1.069 to 1.558], p = 0.008); HLA DR on HSC: (OR [95% CI]: 0.539 [0.343 to 0.846], p = 0.007); Plasmacytoid DC %DC: (OR [95% CI]: 0.610 [0.462 to 0.806], p < 0.001). And sensitivity analyses confirmed the robustness of the main findings.
MR analysis has revealed the causal relationship between immune cells and primary liver cancer through genetic methods. These findings could assist in clinical decision-making and provide new directions for the treatment and research of primary liver cancer.
原发性肝癌是全球最常见的致命恶性肿瘤之一。观察性研究表明，免疫细胞与原发性肝癌密切相关，然而，由于反向因果关系和混杂变量等问题，这种关联的因果方向和程度仍不清楚。因此，本研究旨在探讨免疫细胞与原发性肝癌（包括肝细胞癌（HCC）和肝内胆管癌（ICC））之间的潜在因果关联。
使用来自731种免疫性状和原发性肝癌的全基因组关联研究（GWAS）的汇总统计数据进行两样本孟德尔随机化（MR）分析。原发性肝癌数据集共有456,348名受试者，其中123例HCC病例和456,225名对照，以及104例ICC病例和456,244名对照，均为欧洲血统。评估因果关系的主要方法是逆方差加权（IVW），采用敏感性分析来检验异质性和多效性。
两种免疫表型与HCC风险显著相关：CD45RA + CD4 + 细胞上的CD3（比值比[95%置信区间]：1.334[1.077至1.651]，p = 0.008），单核细胞上的CD80（比值比[95%置信区间]：0.578[0.397至0.844]，p = 0.004）。此外，六种免疫表型被确定与ICC风险显著相关：自然杀伤细胞（NK）上的侧向散射光A（SSC-A）（比值比[95%置信区间]：1.685[1.166至2.436]，p = 0.006）；CD28 - CD8br细胞上的CD3（比值比[�5%置信区间]：1.826[1.206至2.766]，p = 0.004）；初始CD4 + 细胞上的CD45RA（比值比[95%置信区间]：1.391[1.119至1.729]，p = 0.003）；静息调节性T细胞（Treg）占CD4 + 细胞的百分比（比值比[95%置信区间]：1.290[至1.558]，p = 0.008）；造血干细胞（HSC）上的人类白细胞抗原DR（HLA DR）（比值比[95%置信区间]：0.539[0.343至0.846]，p = 0.007）；浆细胞样树突状细胞（pDC）占树突状细胞（DC）的百分比（比值比[95%置信区间]：0.610[0.462至0.806]，p < 0.001）。敏感性分析证实了主要发现的稳健性。
MR分析通过遗传方法揭示了免疫细胞与原发性肝癌之间的因果关系。这些发现有助于临床决策，并为原发性肝癌治疗和研究提供新方向。
