Exploring the Causal Relationship between Plasma Metabolites and Liver Cirrhosis: A Mendelian Randomization Study
DOI:
https://doi.org/10.71222/hn53jx22Keywords:
mendelian randomization, liver cirrhosis, metabolites, genomics, metabolomicsAbstract
Liver cirrhosis constitutes a major global health challenge, yet the precise metabolic pathways underlying its development remain inadequately defined. This study employed a bidirectional two-sample Mendelian randomization (MR) framework to rigorously assess the causal association between circulating plasma metabolites and the risk of cirrhosis. We integrated summary-level data for liver cirrhosis from the IEU Open GWAS database with statistics for 1,400 plasma metabolites and ratios obtained from the GWAS catalog. The inverse variance weighted (IVW) method served as the primary analytical tool, supplemented by four additional robust MR techniques. To ensure the reliability of our findings, sensitivity analyses—including tests for pleiotropy, heterogeneity, and leave-one-out validation—were performed. Forward MR analysis identified ten specific metabolites and two metabolite ratios with suggestive causal links to liver cirrhosis. Specifically, eight metabolites exhibited significant positive causal associations (increasing disease risk), while negative causal relationships (suggesting a protective effect) were observed for two metabolites and two metabolite ratios. Conversely, reverse MR analysis indicated no significant causal effect of liver cirrhosis on these metabolic markers. Sensitivity analyses confirmed the absence of significant horizontal pleiotropy or heterogeneity. By merging genomic and metabolomic insights, this study identifies twelve metabolites or ratios causally linked to cirrhosis, providing novel perspectives on metabolic influences and highlighting potential therapeutic targets.References
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