Abstract
Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies. Immune cell signatures (immunophenotypes) and chronic inflammation have been implicated in HCC pathogenesis. This study aimed to investigate the causal role of immune cell traits in HCC using Mendelian randomization (MR) analysis. A total of 731 immunophenotypes were analyzed using various statistical methods, including the inverse variance weighted method, weighted median method, MR-Egger regression, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier, to assess causal relationships and potential pleiotropy. Forward MR analysis revealed that 4 immunophenotypes, CD28 on CD39+ CD8+ T cells, IgD+ CD38- B cell % lymphocytes, CD4+ CD8dim T cell % leukocytes, and HVEM on central memory CD4+ T cells, had potential causal effects on the risk of HCC. Specifically, CD28 on CD39+ CD8+ T cells and IgD+ CD38- B cells showed a protective effect, whereas CD4+ CD8dim T cell % leukocytes and HVEM on central memory CD4+ T cells were identified as risk factors for HCC. Additionally, inverse MR analysis demonstrated a causal relationship between HCC and HVEM cells in central memory CD4+ T cells. These findings provide valuable insights into the complex relationship between immune cell traits and HCC development. Further studies are required to validate these relationships.