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This study investigated how CCM2, a gene linked to coronary artery disease, affects atherosclerosis development at different disease stages. In mice with reduced CCM2 expression, researchers found protective effects against atherosclerosis early in disease progression, including reduced inflammation and monocyte adhesion in endothelial cells. However, this protection reversed at later stages, with increased inflammatory markers and greater atherosclerotic burden after prolonged high-fat diet, a pattern mirrored in human genetic data showing context-dependent associations with coronary artery disease risk.
Why it matters
This research reveals that a single genetic variant can have opposing effects on cardiovascular disease depending on disease stage and metabolic context, which has important implications for precision medicine approaches and patient stratification in cardiovascular disease prevention and treatment.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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 TNF 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.