Context-specific effects of CCM2 on atherosclerosis

Genetic variants in the Cerebral Cavernous Malformation 2 (CCM2) locus are associated with coronary artery disease (CAD), but the role of CCM2 in atherosclerosis is unknown. We previously identified CCM2 through endothelial cell (EC) Perturb-seq as a regulator of transcriptional programs enriched for CAD risk genes, and predicted that reduced CCM2 function would be athero-protective. Here, we integrated human genetics, functional studies in human aortic ECs, and single cell profiling with mouse models of atherosclerosis to define the effects of reduced CCM2 signaling across disease stages. Ccm2+/- mice developed less atherosclerosis after 12 weeks of high-fat, high-cholesterol diet. At baseline, aortic ECs from Ccm2+/- mice exhibited reduced inflammatory transcriptional programs, and CCM2 knockout in human aortic ECs increased KLF2 expression and reduced monocyte adhesion and procoagulant activity. However, this protective phenotype was not sustained during disease progression. After 12 weeks of high-fat, high-cholesterol diet, Ccm2+/- mice exhibited increased circulating TNFα and increased inflammatory programs in aortic ECs and T cells. Consistent with this transition, Ccm2+/- showed increased atherosclerotic burden after 20 weeks of atherogenic diet. Human genetic analyses showed a similar context-dependent association. The lead variant in the CCM2 locus (rs2107732, a missense V53I coding variant in CCM2) was associated with lower CAD risk in the general population but higher CAD risk in clinical trial cohorts enriched for cardiometabolic disease. These results demonstrate how the phenotypic consequences of a CAD-associated gene can depend on disease context and stage.