Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.