Cdkn2a Is an Atherosclerosis Modifier Locus That Regulates Monocyte/Macrophage Proliferation

Abstract

Objective— Common genetic variants in a 58-kb region of chromosome 9p21, near the CDKN2A/CDKN2B tumor suppressor locus, are strongly associated with coronary artery disease. However, the underlying mechanism of action remains unknown. Methods and Results— We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus and the region of homology with the human 9p21 locus. Microarray and transcript-specific expression analyses showed markedly decreased Cdkn2a expression, including both p16 INK4a and p19 ARF , but not Cdkn2b ( p15 INK4b ), in macrophages derived from congenic mice compared with controls. Atherosclerosis studies in subcongenic strains revealed genetic complexity and narrowed 1 locus to a small interval including Cdkn2a/b . Bone marrow (BM) transplantation studies implicated myeloid lineage cells as the culprit cell type, rather than resident vascular cells. To directly test the role of BM-derived Cdkn2a transcripts in atherogenesis and inflammatory cell proliferation, we performed a transplantation study using Cdkn2a +/− cells in the Ldlr −/− mouse model. Cdkn2a -deficient BM recipients exhibited accelerated atherosclerosis, increased Ly6C hi proinflammatory monocytes, and increased monocyte/macrophage proliferation compared with controls. Conclusion— These data provide a plausible mechanism for accelerated atherogenesis in susceptible congenic mice, involving decreased expression of Cdkn2a and increased proliferation of monocyte/macrophages, with possible relevance to the 9p21 human locus.