通过 eQTL 定位识别结直肠癌免疫生物标志物：一项孟德尔随机化和转录组分析研究

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. The identification of effective molecular targets is crucial for advancing precision medicine and prognostic strategies. This study aims to uncover key CRC biomarkers through integrative bioinformatics analyses, providing mechanistic insights for therapeutic development.

We analyzed three CRC datasets from the Gene Expression Omnibus (GEO) database. Expression quantitative trait loci (eQTL) analysis was performed to identify instrumental variables (IVs), which were subsequently used in Mendelian Randomization (MR) analysis with CRC Genome-Wide Association Study (GWAS) data. MR-associated genes were intersected with differentially expressed genes (DEGs) to screen disease-related key genes. Functional enrichment analyses were conducted using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Additionally, immune cell infiltration and gene-immune correlation analyses were performed. Finally, validation was performed using independent GEO, The Cancer Genome Atlas (TCGA) datasets, summary data-based Mendelian randomization (SMR) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in CRC cell lines.

A total of 776 upregulated and 981 downregulated DEGs were identified. Nine key genes were prioritized: ATP13A4, CD1C, METTL7A, SLC18A1, CREB5, CXCR1, GZMB, HECW2, and TEAD2 , predominantly involved in cytokine receptor interaction pathways. CIBERSORT analysis revealed increased activated CD4+ memory T cells and M0 macrophages, alongside decreased plasma cells and natural killer (NK) cells in CRC. Key genes demonstrated significant correlation with immune cell subsets ( e.g. , neutrophils, mast cells), highlighting their role in CRC immunobiology. Validation via SMR and qRT-PCR assays demonstrated significant dysregulation of four target genes ( CXCR1 , HECW2 , ATP13A4 ) ( P < 0.05). DISCUSSION: This study suggests that CXCR1 , HECW2 , and ATP13A4 may be involved in CRC development, providing a reference for targeted and immunotherapy research.