Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Atherosclerosis is a complex inflammatory process driven by plaque formation in the major elastic arteries and often leads to reduced blood flow, coronary artery disease (CAD), myocardial infarction and stroke. CAD progression involves complex interactions and phenotypic plasticity within and between distinct vascular and immune cell lineages. Several single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures however there remains variability on the reported cell phenotypes in humans. In this study we meta-analyzed scRNA-seq datasets across four publications to create a comprehensive map of human atherosclerosis cell diversity. We applied standardized QC, processing, and integration benchmarking to harmonize 118,578 high-quality cells for this atlas. Beyond characterizing vascular and immune cell diversity, we derived insights into smooth muscle cell (SMC) phenotypic modulation through pseudotime, transcription factor activity inference and cell-cell communication analyses. We also integrated genome-wide association study (GWAS) data to identify etiologic cell types for GWAS diseases and traits, which uncovered a critical role for modulated SMC phenotypes in CAD and coronary artery calcification. Finally, we identified candidate markers (e.g., CRTAC1) of synthetic and osteochondrogenic SMCs that may serve as proxies of atherosclerosis progression. Together, this represents an important step towards creating a unified cellular map of atherosclerosis to inform cell state-specific mechanistic and translational studies of cardiovascular diseases.