ArticleDiscover oncology2025
Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease.
Article in Discover oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe causal relationships between hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD) remain unclear. This study investigated bidirectional causality between HCC and NAFLD using Mendelian randomization, and evaluated liver-related mortality risk in NAFLD patients through meta-analysis.
methodsWe performed bidirectional two-sample Mendelian randomization using genome-wide association study data (775 HCC cases, 1,332 controls; 8,434 NAFLD cases, 770,180 controls). Multiple analytical methods included inverse variance weighted, MR-Egger, and weighted median approaches. Meta-analysis included 8 studies with 577,921 participants examining liver-related mortality in NAFLD versus non-NAFLD populations.
resultsMendelian randomization analysis revealed no significant causal relationships between HCC and NAFLD in either direction, with effect estimates consistently clustering around zero across all methods. Meta-analysis demonstrated significantly increased liver-related mortality risk in NAFLD patients (HR = 3.99, 95% CI: 2.11-7.55, P < 0.0001) with substantial heterogeneity (I² = 92.9%).
conclusionThis study provides evidence against strong bidirectional causal relationships between genetic predisposition to HCC and NAFLD. However, NAFLD patients show a four-fold increased risk of liver-related mortality, highlighting the clinical importance of NAFLD as a predictor of adverse liver outcomes.
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