Multi-omic insight into the molecular networks of macrophage polarization in the pathogenesis of atrial fibrillation

The intimate association between macrophage polarization and atrial fibrillation (AF) has garnered substantial research interest, yet the epigenetic, transcriptional, and proteomic regulation of immune-mediated atrial remodeling remain elusive. This study aims to elucidate the causal relationship between macrophage polarization and AF by integrating multi-omics datasets.

This study conducted an analysis utilizing genes pertinent to macrophage polarization from the GeneCards database, alongside QTL summary statistics for gene expression (eQTL), DNA methylation (mQTL), and protein expression (pQTL). Through summary-data-based Mendelian randomization (SMR), we explored associations between macrophage polarization-related genes and AF. Colocalization analyses were performed to identify common causal variants.

We discovered 52 mQTLs, 8 eQTLs, and 2 pQTLs linked to AF risk. Specifically, the genes DNMT3A (cg17742416, cg08485187, cg13558695, and cg08493294) and PRKCA (cg22127848) were associated with AF risk both in terms of gene expression (OR < 1) and methylation levels (OR > 1), with this association supported by colocalization. Further integrated analysis suggests that DNA methylation occurring at CpG sites in DNMT3A and PRKCA directly regulates gene expression (OR < 1) via cis-regulatory mechanisms, thereby influencing individual susceptibility to AF. Tissue-specific SMR analysis further supported the potential relevance of PRKCA in atrial appendages, where its expression levels strongly correlated with AF.

Employing a SMR approach, we have identified DNMT3A and PRKCA as candidate genes potentially implicated in the pathogenesis of AF. These findings pave the way for novel insights into early prevention and therapeutic strategies for AF.

Not applicable.