Causal association of nonalcoholic fatty liver disease with 22 extrahepatic cancers: A Mendelian randomization study

Abstract Aim It is unclear whether nonalcoholic fatty liver disease (NAFLD) acts as a direct contributing factor to multiple extrahepatic cancers. We aimed to systematically investigate the causal relationships of NAFLD with extrahepatic cancers. Methods We conducted a two‐sample Mendelian randomization analysis to assess the causal effects of NAFLD on 22 extrahepatic cancers. We examined the association of NAFLD with extrahepatic cancers using multiple methods in the largest genome‐wide association study meta‐analysis to date. We also replicated the analyses and performed two independent sensitivity analysis in the largest genome‐wide association study of UK Biobank. Results Using the weighted median method, genetically predicted NAFLD was significantly associated with female breast cancer risk (odds ratio [OR] 15.99; 95% confidence interval [CI] 9.58–26.69). Genetically predicted NAFLD is associated with cervical and laryngeal cancers using the inverse variance weighting method, and the ORs were 2.44 (95% CI 1.43–4.14) and 1.94 (95% CI 1.35–2.78), respectively. We observed that patatin‐like phospholipase domain‐containing protein 3‐driven and transmembrane 6 superfamily member 2‐driven NAFLD were associated with increased risks of leukemia, lung cancer, and prostate cancers (all with p < 0.05). Furthermore, we confirmed the causal association between NAFLD and breast cancer using five known single‐nucleotide polymorphisms of NAFLD and six genome‐wide association study‐identified variants. The ORs of the weighted median estimator was 10.76 (95% CI 8.27–13.98) and 10.76 (95% CI 8.25–14.04), respectively ( p < 0.001). Conclusion Genetically predicted NAFLD is associated with an increased risk of female breast cancer, as well as cervical, laryngeal, leukemia, lung, and prostate cancers.