Decoding Restenosis Risk After CABG: A Combined Transcriptomic and Mendelian Randomization Analysis

Background Restenosis following coronary artery bypass grafting (CABG), especially in saphenous vein grafts (SVGs), remains a significant long-term complication, affecting up to 20% of cases. While technical and biological contributors are well characterized, non-technical lifestyle and clinical risk factors remain underexplored due to limitations in observational research. This study aimed to identify non-technical risk factors contributing to restenosis after CABG by integrating transcriptomic data and Mendelian randomization analysis. Methods We analyzed microarray data (GSE241205) to identify differentially expressed genes (DEGs) between occluded and unoccluded SVGs. Enrichment analysis via DAVID identified key biological pathways. The most enriched pathway—immune system activation—was used as the outcome in two-sample Mendelian randomization using GWAS summary statistics for 15 lifestyle and metabolic exposures. Causal estimates were calculated using inverse variance weighted (IVW) method, with sensitivity analyses for pleiotropy and heterogeneity. Results Among 4,443 DEGs, IGKV3D-20 (log2FC 14.02) and OTC (log2FC -7.29) were the most significantly altered. Immune system activation, particularly complement activation, emerged as the dominant pathway. Mendelian randomization revealed high LDL (>159 mg/dL; OR = 12.57), total cholesterol (>200 mg/dL; OR = 11.20), smoking (16 cigarettes/day; OR = 9.98), and alcohol intake (250 ml/day; OR = 3.24) significantly increased pathway activation. Protective factors included physical exercise (30 mins/day; OR = 0.22), HDL (<40 mg/dL; OR = 0.41), aspirin (OR = 0.83), and clopidogrel (OR = 0.24). No significant pleiotropy or heterogeneity was observed. Conclusion Immune activation plays a central role in restenosis after CABG. Modifiable non-technical factors—particularly lipid profile and lifestyle behaviors—contribute significantly and may guide preventive strategies.