Integrative multi-omics analysis of macrophage polarization-related genes in atherosclerosis development

The differentiation of macrophages into foam cells is a hallmark of atherosclerotic plaques, and macrophage polarization is a key driver of disease progression, yet the underlying genetic mechanisms remain poorly understood. We employed summary data-based Mendelian randomization (SMR) combined with transcriptomic validation to explore causal relationships and validate findings at the tissue level.

We integrated multi-omics data, including DNA methylation (mQTLs), gene expression (eQTLs), and protein expression (pQTLs), from GeneCards and GWAS summary statistics from FinnGen and UK Biobank. SMR and colocalization analyses were used to identify causal associations. Tissue-specific validation was conducted using eQTL data from artery tissues, and transcriptome analysis was performed using GEO datasets to confirm gene expression patterns in atherosclerotic tissues, followed by confirmation in clinical samples. The function of key genes were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.

SMR and colocalization analyses identified 41 methylation sites, 2 genes (DNMT3A and DLGAP5), and 1 protein associated with atherosclerosis. Specifically, methylation site cg10130446 in DLGAP5 was negatively correlated with atherosclerosis, while sites cg08485187 and cg17742416 in DNMT3A were positively associated. Tissue-specific validation revealed that SIRT6 gene expression was linked to atherosclerosis risk in aortic and tibial artery tissues. Transcriptome analysis from GEO database and blood samples confirmed elevated DLGAP5 and SIRT6 expressions.

This study integrates SMR with transcriptomic validation to reveal causal links between macrophage polarization-related genes and atherosclerosis. Key genes DNMT3A, DLGAP5, and SIRT6 were identified as significant candidate regulatory factors. Tissue-specific validation and GEO-based transcriptome analysis provided robust evidence supporting these findings, highlighting the importance of macrophage polarization in atherosclerosis pathogenesis and offering new insights for therapeutic intervention.