Abstract Body: A single nucleotide missense polymorphism (rs1800449, R158Q) in the propeptide domain of lysyl oxidase (LOX-PP) is associated with increased risk of coronary disease independent of changes in plasma lipid levels. Although the enzymatic function of LOX has an essential role for the cross-linking of extracellular matrix proteins in connective tissues, whether and how LOX-PP R158Q contributes to the development of atherosclerosis has not been clearly established. In this study, we characterized atherosclerotic plaque lesions of both human and mouse arteries and found that LOX is mainly expressed by vascular smooth muscle cells (VSMCs). Using complementary mouse models, we provide evidence that the R158Q polymorphism promotes atherosclerosis and induces proliferation of macrophages and VSMCs without altering LOX enzymatic activity. Using single-cell RNA sequencing, we found that the transcriptional program of atherosclerotic plaques from mice harboring R158Q was strongly enriched for proliferation- and calcification-related genes in a regionally distinct manner. Together, these results establish an enzymatically-independent proatherogenic role for the LOX-PP and suggest its potential as a novel therapeutic target.