Abstract

BackgroundAtherosclerosis shows vascular bed specificity, yet research has focused on coronary arteries, leaving the causal genetics and immune cell-specific mechanisms of carotid plaque (CP) unexplored. This study aims to unbiasedly identify CP candidate genes and evaluate their therapeutic potential.MethodsTwo-sample MR analysis was performed using data from 14 peripheral blood immune cell types and two GWAS datasets for carotid plaque, followed by colocalization analysis to prioritize causal genes. A human carotid plaque single-cell RNA-seq dataset was then integrated to examine cellular expression patterns, cell-cell communication, and functional enrichment. In vitro experiments using THP-1-derived macrophages and Jurkat T cells were conducted to validate the function of the key gene. Molecular docking and PheWAS were employed to evaluate its translational potential and possible pleiotropic associations.Results22 candidate genes for CP were identified. LIPA_Mono_C showed a consistent causal association with increased CP risk in two independent GWAS datasets. Single-cell RNA sequencing confirmed that LIPA was highly expressed in mononuclear phagocytes of CP tissues, and CellChat analysis suggested a potential SPP1-CD44-mediated interaction between LIPA-expressing mononuclear phagocytes and T cells. In silico knockout of LIPA revealed significant enrichment of the complement and coagulation cascades. In vitro experiments verified that oxidized low-density lipoprotein upregulated LIPA in macrophages in a time- and dose-dependent manner. LIPA knockdown alleviated lipid accumulation, suppressed complement activation, attenuated SPP1 expression, and reduced SPP1/CD44-associated T-cell functional readouts in vitro. Additionally, dorsomorphin reduced oxLDL-induced LIPA upregulation and lipid accumulation in macrophages.ConclusionOur integrative genetic and transcriptomic approach prioritizes LIPA as a mononuclear phagocyte-enriched candidate gene for CP. Functional and