The Causal Impact of Immune Cell Dynamics on liver failure: An Investigation via Mendelian Randomization (MR) Analysis

Background: Liver failure is a critical clinical condition with complex pathophysiology, where the role of immune cells has been increasingly recognized. However, establishing causality between immune cell activity and liver failure has been challenging. We aimed to investigate the causal role of specific immune cell populations in the development of liver failure using Mendelian randomization (MR) techniques. Methods: Genetic data from the Genome-wide association study (GWAS) database, focusing on 731 immunophenotypes and a liver failure dataset was utilised. Single nucleotide polymorphisms (SNPs) associated with immune cell exposures were identified and used as instrumental variables. MR analyses were performed using the TwoSampleMR package in R, employing various MR techniques, including weighted median, MR Egger, inverse-variance weighted (IVW), and others. The robustness of the MR findings was assessed through heterogeneity, pleiotropy, and leave-one-out sensitivity analyses. Results: Our MR study revealed significant causal associations between several immune cell populations and liver failure. Notably, genetic variants associated with CD28 on CD39+ CD4+ T cells and CD3 on CD39+ secreting T Reg cells were found to be causally linked to an increased risk of liver failure. The IVW MR method, which has been previously validated for its performance, provided the most consistent results across immune cell exposures. Conclusion: Our findings suggest a direct causal role for specific immune cells in liver failure, offering potential targets for future therapeutic strategies.