Identification of key genes and immune mechanisms in atrial fibrillation: An observational bioinformatics and single-cell transcriptome study

Atrial fibrillation (AF) is a common arrhythmia associated with immune dysregulation and complex molecular mechanisms. This observational bioinformatics study aimed to identify key genes involved in AF, explore their functional roles, and uncover potential therapeutic targets. Public gene expression datasets (GSE79768 and GSE41177) and single-cell ribonucleic acid sequencing datasets (GSE224995 and GSE261170) were analyzed. Differentially expressed genes were screened using the limma package, and enrichment analyses (Gene Ontology/Kyoto Encyclopedia of Genes and Genomes) were conducted. Key genes were selected via Least Absolute Shrinkage and Selection Operator regression and validated in external datasets. Immune cell infiltration was assessed using the CIBERSORT algorithm, while single-cell ribonucleic acid sequencing analysis provided cell-type-specific expression and cell-cell interaction insights. We identified 85 differentially expressed genes, among which LBH, C8orf4, INPP5A, CHGB, and B3GALTL showed consistent differential expression and diagnostic performance (area under the curve ≥ 0.70). Immune analysis revealed a pro-inflammatory microenvironment in AF, characterized by elevated neutrophils and classically activated macrophages and reduced alternatively activated macrophages and Tregs. Single-cell analysis confirmed the cell-specific expression of key genes and highlighted intercellular communication between immune and stromal cells. Our findings suggest that immune imbalance and mitochondrial dysfunction are central to AF pathogenesis. The identified genes may serve as promising diagnostic biomarkers and therapeutic targets for AF.