title: 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.
  
  
  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 proinflammatory monocytes, and increased monocyte/macrophage proliferation compared with controls.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Kuo
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Scott
authors.initials: S
authors.lastname: Sayers
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
authors.forename: Jaeger Z
authors.initials: JZ
authors.lastname: Davis
authors.forename: Janakiraman
authors.initials: J
authors.lastname: Krishnamurthy
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D019942:Genes, p16; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011973:Receptors, LDL