Assessing the causal relationship between mitochondria-associated proteins and chronic liver diseases：a comprehensive Mendelian randomisation study

Abstract

Abstract Mitochondria-related proteins (MRPs) and chronic liver diseases have been linked in various studies, although their causal relationship has not been elucidated. In this study, we investigated the causal associations between MRPs and non-alcoholic fatty liver disease (NALFD), liver cirrhosis and hepatocellular carcinoma (HCC) by two-sample bidirectional Mendelian randomisation(MR) analysis.The random-effect Inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and Weighted Median (WM) as complementary analyses. Cochran Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out analysis were used for sensitivity analyses. In addition, we performed bonferroni correction,multivariable MR analysis(MVMR),reverse causality detection and protein–protein interaction(PPI) network to enrich the results of this study.After rigorous genetic variant selection, IVW, sensitivity analysis, 3 genetically determined MRPs were significantly associated with NAFLD [MRPL33 (OR: 1.06, 95% CI: 1.00-1.11, p = 0.0284), MRPL34 (OR: 0.88, 95% CI: 0.78–0.98, p = 0.0294) and FARS2 (OR : 0.90, 95% CI: 0.84–0.97, p = 0.0120)], 2 MRPs were significantly associated with liver cirrhosis[MICU1 (OR: 1.11, 95% CI: 1.00-1.22, p = 0.0337) and NUDT8 (OR: 1.16, 95% CI: 1.03–1.30, p = 0.0096)], and 4 MRPs were significantly correlated with HCC [MRPL32 (OR: 0.62, 95% CI: 0.39–0.99, p = 0. 0492), MRPL33 (OR:1.29, 95% CI: 1.07–1.55, p = 0.0063), SCO1 (OR:0.56, 95% CI. 0.38–0.83, p = 0.0036) and SIRT5 (OR:0.71, 95% CI: 0.53–0.96, p = 0.0283)].Our findings provide a new perspective on the exploration of the underlying mechanisms of chronic liver diseases. However, further studies are still needed to explore the mechanisms of possible potential causal associations between MRPs and chronic liver diseases.