Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease
Abstract Background The 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 p...
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Springer
2025-08-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-03350-0 |
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| author | Tielong Zhao Yanglieguang Lou |
| author_facet | Tielong Zhao Yanglieguang Lou |
| author_sort | Tielong Zhao |
| collection | DOAJ |
| description | Abstract Background The 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. Methods We 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. Results Mendelian 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%). Conclusion This 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. |
| format | Article |
| id | doaj-art-4cc700dec4c84e46aae591ad0af561c0 |
| institution | DOAJ |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-4cc700dec4c84e46aae591ad0af561c02025-08-20T03:06:50ZengSpringerDiscover Oncology2730-60112025-08-0116111310.1007/s12672-025-03350-0Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver diseaseTielong Zhao0Yanglieguang Lou1Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing UniversityDepartment of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing UniversityAbstract Background The 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. Methods We 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. Results Mendelian 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%). Conclusion This 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.https://doi.org/10.1007/s12672-025-03350-0Hepatocellular carcinomaNon-alcoholic fatty liver diseaseMendelian randomizationMeta-analysisLiver-related mortality |
| spellingShingle | Tielong Zhao Yanglieguang Lou Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease Discover Oncology Hepatocellular carcinoma Non-alcoholic fatty liver disease Mendelian randomization Meta-analysis Liver-related mortality |
| title | Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease |
| title_full | Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease |
| title_fullStr | Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease |
| title_full_unstemmed | Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease |
| title_short | Bidirectional Mendelian randomization analysis and systematic meta-analysis of causal relationships between hepatocellular carcinoma and non-alcoholic fatty liver disease |
| title_sort | bidirectional mendelian randomization analysis and systematic meta analysis of causal relationships between hepatocellular carcinoma and non alcoholic fatty liver disease |
| topic | Hepatocellular carcinoma Non-alcoholic fatty liver disease Mendelian randomization Meta-analysis Liver-related mortality |
| url | https://doi.org/10.1007/s12672-025-03350-0 |
| work_keys_str_mv | AT tielongzhao bidirectionalmendelianrandomizationanalysisandsystematicmetaanalysisofcausalrelationshipsbetweenhepatocellularcarcinomaandnonalcoholicfattyliverdisease AT yanglieguanglou bidirectionalmendelianrandomizationanalysisandsystematicmetaanalysisofcausalrelationshipsbetweenhepatocellularcarcinomaandnonalcoholicfattyliverdisease |