Causal associations between platelet count, alcohol consumption, and the risk of liver hepatocellular carcinoma based on a Mendelian randomization study
Authors: Yu Lihua , Wang Leisheng , Xue Yuzheng , Ren Yilin , Liu Tianhao , Hu Hao 
Published: May 2024

Background and aimsLiver hepatocellular carcinoma (LIHC) exhibits a multifactorial etiology, insidious onset, and a significantly low 5-year survival rate. We aimed to evaluate the causal impact of exposure factors (Alzheimer’s disease, platelet count, ambidextrousness, cigarettes smoked per day, alcohol consumption, and endocarditis) on the risk of LIHC using a two-sample Mendelian randomization (MR) study.MethodsIndependent single nucleotide polymorphisms (SNPs) strongly associated with Alzheimer’s disease, platelet count, ambidextrousness, daily cigarette consumption, alcohol intake, and endocarditis were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). Genetic summary statistics for LIHC came from a GWAS that included 168 cases and 372,016 controls of European individuals. Multivariable MR analyses were performed to find the causal association between 6 exposure factors and LIHC risk. The inverse-variance weighted (IVW)-MR was employed as the primary analysis, and the MR-Egger regression, LASSO regression, and weighted Median approaches were performed as complementary analyses.ResultsMultivariable MR analysis showed causal association between Alzheimer’s disease [Odds ratio (OR) = 0.9999, 95% confidence intervals (CI) = 0.9998-0.9999, p = 0.0010], platelet count (OR = 0.9997, 95% CI = 0.9995-0.9999, p = 0.0066), alcohol consumption (OR = 0.9994, 95% CI = 0.9990-0.9999, p = 0.0098) and the LIHC outcome. After IVW-MR, MR-Egger and LASSO tests, the results are still significant. Next, we used different MR Methods to analyze platelet count, alcohol consumption, and Alzheimer’s disease separately. Moreover, both funnel plots and MR-Egger intercepts provided compelling evidence to refute the presence of directional pleiotropy in the association between platelet count, alcohol consumption, Alzheimer’s disease and the risk of LIHC. The IVW-MR analysis revealed a significant causal association between an elevated platelet count and a reduced risk of LIHC (OR = 0.9996, 95% CI= 0.9995-0.9998, p = 0.0005). Similarly, the analysis of weighted median revealed a negative correlation between platelet count and the risk of LIHC (OR = 0.9995, 95% CI = 0.9993-0.9999; p = 0.0160). Conversely, we observed a positive causal effect of alcohol consumption on the incidence of LIHC (OR = 1.0004, 95% CI = 0.9999-1.0009). However, no significant causal relationship was found between alcohol assumption, Alzheimer’s disease, and LIHC susceptibility.ConclusionsA significant causal relationship exists between platelet count, alcohol consumption, Alzheimer’s disease, and an increased risk of LIHC. The study presents compelling evidence for a genetically predicted decreased susceptibility to LIHC based on platelet count. The research implies that elevated platelet count may serve as a protective mechanism against LIHC. These findings may inform clinical strategies for LIHC prevention