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Background From cross-sectional studies we have learned that composition of atherosclerotic plaques differs between individuals, and this contributes to the inter-individual differences in susceptibility to incident coronary and cerebral events. In pathological studies the extent and type of atherosclerosis is commonly assessed based on histological plaque characteristics that are linked to plaque rupture and erosion. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. Objectives We investigated the genetics of the plaque through multivariate and integrative genome-wide analyses (GWAS) of individual plaque characteristics. Methods We included carotid endarterectomy patients from the Athero-Express Biobank Study (n=2,124) with high-density imputed data and extensive histochemical plaque phenotyping available. We used slideToolKit to quantify the number of endothelial cells, macrophages and smooth muscle cells (SMCs), and manually assessed the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. We ran GWAS on all traits correcting for age, sex, array used, and genetic ancestry. Results We identified 3 loci that significantly associate with CD68+ macrophages and ACTA2+ SMCs, p&amp;lt;5x10–8. Statistical finemapping revealed 9 variants in the 95% credible set and functional annotation linked these to genes associated with malignant neoplasms, circulating cholesterol, and transmembrane proteins, suggesting an effect on cellular proliferation and cholesterol metabolism. Conclusions We provide evidence for 3 loci that modulate plaque composition through macrophages and smooth muscle cell plaque proliferation and cell-cell interactions. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): European Research Area Network on Cardiovascular Diseases (ERA-CVD, druggable-MI-genes),China Scholarship Council

A multivariate analysis identifies genetic loci associated with atherosclerotic plaque composition and cardiovascular disease trajectory