Abstract
BACKGROUND: Coronary heart disease (CHD) is a leading cause of cardiovascular mortality worldwide, with its pathogenesis being complex and not yet fully understood. The rapid development of genomics, especially in epigenetic research, has provided essential tools for identifying new pathogenic targets. This study is aimed at systematically exploring the molecular mechanisms of CHD using protein quantitative trait locus (pQTL) data and multiomics Mendelian randomization (MR) approaches, with a specific focus on the epigenetic regulation of the key gene ITGB7. METHODS: The study first integrated 1812 cis-pQTL data with CHD GWAS data to perform a two-sample MR analysis, identifying protein-coding genes significantly associated with CHD. Transcriptomic data were then used to validate the differential expression of these genes. Subsequently, a two-step MR mediation analysis was conducted to explore the upstream regulatory effect of DNA methylation on the key gene ITGB7, as well as the potential mediating roles of ITGB7 on downstream immune cells and plasma metabolites. RESULTS: MR analysis identified 17 genes significantly positively associated with CHD, with PCSK9 and ITGB7 showing significant upregulation in the peripheral blood of CHD patients. Mediation analysis revealed that the DNA methylation site cg14524975 (beta_p = 45.64%) significantly increased the risk of CHD by positively regulating the expression of ITGB7. In downstream mechanisms, ITGB7 significantly promoted CHD progression by regulating immune cells, such as CD4+ CD8dim AC (beta_p = 12.04%), and plasma metabolites, including N,N-dimethylalanine (beta_p = 18.96%), benzoate-to-oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio (beta_p = 34.63%), and serine-to-threonine ratio (beta_p = 12.58%). CONCLUSION: This study identifies ITGB7 as a novel pathogenic gene for CHD and reveals its multiomics mechanisms in promoting CHD development through DNA methylation regulation, immune response activation, and metabolic pathway disruption. The findings provide valuable theoretical insights and potential biomarkers for the pathogenesis and targeted intervention of CHD.