Abstract
BACKGROUND: Platelet indices are non-invasive biomarkers used to assess disease status. Observational studies have shown that platelet indices are related to liver cancer. However, the specific relationship between the two is still inconclusive. We conducted a Mendelian randomization (MR) study to investigate the causal relationship between platelet indices and liver cancer. METHODS: We identified 2 cancer outcomes (liver cell carcinoma, malignant neoplasm of liver and intrahepatic bile ducts) from genome-wide association studies (GWAS). We used inverse variance weighted (IVW) method as the main method. In order to evaluate the potential horizontal pleiotropy or heterogeneity, sensitivity analyses were examined via MR-Egger regression, heterogeneity test, pleiotropy test. RESULTS: Two-Sample MR analysis showed there were causal relationships between platelet indices and liver cancer. The mean platelet volume was positively associated with hepatocellular carcinoma (HCC) risk, while platelet count was inversely correlated with HCC risk, platelet endothelial cell adhesion molecule levels were significantly related to an increased malignant neoplasm of liver and intrahepatic bile ducts risk. In addition, we conducted reverse MR analyses and found that malignant neoplasm of liver and intrahepatic bile ducts was positively associated with platelet count and platelet crit, but negatively correlated with platelet distribution width. Following multivariable mendelian randomization adjustments for potential confounding variables, the independent effects of platelet indices on HCC were not statistically significant. CONCLUSIONS: The bidirectional causal relationship between platelet indices and liver cancer may be mediated by confounding factors such as liver cirrhosis. Further validation through mediation MR analyses or larger-scale replication studies is required to elucidate these causal pathways.