Genetically predicted immune cells mediates the association between hepatocellular carcinoma and inflammatory proteins: a Mendelian randomization study.

BACKGROUND

Hepatocellular carcinoma (HCC) currently poses a formidable threat to human life and health, and an observable increase in the number of deaths is evident year by year. Currently, surgical resection stands as the foremost treatment modality; however, recurrence remains a persistent challenge, posing a significant barrier to the long-term prognosis for individuals diagnosed with HCC. Studies indicated that the risk of HCC may be influenced by inflammatory proteins and immune cells, but the associations between inflammatory proteins, immune cells, and HCC remained unclear.

METHODS

The investigation integrated data from 731 types of circulating immune cells and 91 inflammatory proteins, alongside a cohort involving 456,348 participants (comprising 456,220 controls and 128 cases) sourced from genome-wide association studies (GWAS). The principal objective of our research was to assess the potential causal association between inflammatory proteins and HCC by bidirectional univariate MR (UVMR) analysis. Furthermore, the total genetic prediction effect of immune cells-mediating inflammatory proteins on the likelihood of developing HCC was investigated by a two-step multivariable MR (MVMR).

RESULTS

Our results indicated that 2-positive inflammatory proteins (IL-17A and TNF-β) suggest a potential causal relationship on HCC, and HCC could affect FGF-21 by bidirectional UVMR analysis. Additionally, four immune cell types (CD25 on IgD+ CD38dim B cells, CD4 on CD39+ secreting CD4 regulatory T cells, CD25 on B cells, and CD25 on IgD+ B cells) exhibited an inverse relationship with the risk of HCC. Moreover, two inflammatory proteins demonstrated dual effects on HCC risk through modulation-either decreasing or increasing-the aforementioned four immune cell types, each with varying proportions of mediation effects as analyzed through two-step mediation MR analysis.

CONCLUSION

This study revealed the potential causality between inflammatory proteins, immune cells, and HCC risk by MR analyses, which may potentially offer a deeper comprehension for the risk of HCC and the interaction between inflammatory proteins, immune cells and HCC and may help to seek new biomarkers for predicting the likelihood of developing HCC.