Mendelian randomization analysis reveals the potential of the IKZF1 gene as a therapeutic target in colorectal cancer.

Introduction: Colorectal cancer (CRC) is a global health burden, highlighting the urgent need for the discovery of new biomarkers and therapeutic targets. This study integrates genetic epidemiology methods, such as Mendelian randomization (MR), with GWAS data to predict treatment efficacy and identify novel CRC therapeutic targets.

Methods: We utilized cis-eQTL data from the eQTLGen consortium and CRC GWAS data from the IEU Open GWAS database. MR analysis was conducted via the R package TwoSampleMR. Bayesian colocalization analysis was applied to identify shared genetic effects between CRC risk factors and potential therapeutic targets. Phenome-wide association study (PheWAS), protein-protein interaction (PPI) network construction, and enrichment analyses were performed to elucidate the functional profiles of the targets. Molecular docking and dynamics simulations were employed to evaluate the therapeutic potential of the identified targets.

Results: MR analysis identified 60 genes associated with CRC risk. Our analysis identified IKZF1 as a significant therapeutic target through colocalization analysis. The PheWAS results revealed no significant genomic correlations for IKZF1, suggesting its potential as a specific therapeutic target. PPI and enrichment analyses highlighted the role of IKZF1 in epigenetic regulation and transcriptional control. Molecular docking and dynamics simulations confirmed the strong binding affinities of potential drugs with IKZF1.

Conclusion: This study identified IKZF1 as a promising therapeutic target for CRC through MR and colocalization analyses. The target's association with immune modulation and epigenetic mechanisms, supported by molecular docking and dynamics simulations, positions IKZF1 as a key player in advancing precision CRC therapies, warranting further clinical investigation.