Mendelian Randomization Identifies Putative Aging‐Related Causal Genes With Diagnostic Potential in Ulcerative Colitis

BACKGROUND: Aging-related immunosenescence increases the risk of ulcerative colitis (UC), and investigating aging-related causal genes in UC patients may aid in deciphering the molecular pathophysiology of UC. This study aims to identify aging-related causal genes and explore their diagnostic value and underlying mechanisms in UC. METHODS AND MATERIALS: Colonic transcriptome data, aging-related genes, genome-wide association studies (GWAS) data, and cis-expression quantitative trait loci (cis-eQTL) data were collected from databases. Aging-related differentially expressed genes (ARDEGs) were identified, and functional enrichment analysis was performed. Summary-data-based Mendelian randomization (SMR) analysis and validation were performed to identify putative aging-related causal genes (PARCGs). The expression levels and diagnostic efficacies of the PARCGs were evaluated and validated. Their correlations with immune infiltration were explored. RESULTS: 371 ARDEGs were identified that were mainly involved in biological functions related to immunity, inflammation, and senescence. Through SMR, five genes (IRF1, CTSB, IL24, ME2, ERBB2) were first selected as latent aging-related causal genes (LARCGs), and their expression levels were causally correlated with the risk of UC (IRF1, OR: 3.23, 95% CI: 1.80-5.77; CTSB, OR: 1.30, 95% CI: 1.14-1.47; IL24, OR: 1.66, 95% CI: 1.24-2.22; ME2, OR: 0.75, 95% CI: 0.63-0.89; ERBB2, OR: 0.21, 95% CI: 0.10-0.45). By replicating SMR analysis using the two additional UC GWAS data, three PARCGs (IRF1, ME2, ERBB2) were further determined. IRF1 was upregulated, while ME2 and ERBB2 were downregulated in UC, and all three PARCGs showed diagnostic potential for UC. Furthermore, correlation analysis revealed multiple correlations between the PARCGs and immune cells. CONCLUSION: We identified three aging-related genes (IRF1, ME2, ERBB2) through SMR for the first time that are causally correlated to the risk of UC. Further analysis revealed their diagnostic potential and explored their correlation with immune infiltration in UC.