Association of IGHG1 with carotid plaque progression and NK Cell-related immune features: Insights from bulk and single-cell transcriptomics

Background: The progression of carotid plaques is closely associated with immune dysregulation. This study aimed to identify key natural killer (NK) cell–related genes and to explore their immune microenvironment using bulk and single-cell transcriptomic data. Methods: Differential expression analysis was performed based on the transcriptomic dataset GSE43292. Key gene modules were identified using weighted gene co-expression network analysis (WGCNA). NK cell–related hub genes were further screened using Lasso and logistic regression, followed by validation in an external cohort. The expression profile of IGHG1 and intercellular communication of NK cells were assessed using single-cell RNA sequencing (scRNA-seq). Pseudotime trajectory analysis was conducted with Monocle 2, and IGHG1-associated signaling pathways were explored through gene set enrichment analysis (GSEA). Results: Four candidate genes were screened, and IGHG1 was the only independent risk factor. IGHG1 was significantly upregulated in advanced-stage plaques and demonstrated high predictive performance (AUC = 0.831; external AUC = 0.911). In the scRNA-seq dataset analyzed in this study, IGHG1 signal was mainly detected in the annotated NK-cell cluster. However, because IGHG1 is canonically associated with B-lineage and plasma cells, this observation should be interpreted cautiously in the context of SingleR/CellMarker-based annotation. Two NK-related subclusters were identified, showing inferred intercellular interactions predominantly involving the PPIA–BSG ligand–receptor pair. Pseudotime analysis revealed a transient high expression of IGHG1 during the transition from precursor to mature NK cells. GSEA indicated that IGHG1 was involved in the T cell receptor signaling pathway and NK cell–mediated cytotoxicity pathway. Conclusion: IGHG1 is a key gene closely associated with the progression of carotid plaques and was linked to NK cell-related immune features in our analyses. Given the canonical association of IGHG1 with B-lineage/plasma cells and the limitations of automatic annotation, its cellular origin and functional relevance require further validation.