title: Effect of 9p21.3 coronary artery disease locus neighboring genes on atherosclerosis in mice.
abstract: BACKGROUND
  The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap, the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b, in atherosclerosis using knockout mice models.
  
  
  RESULTS
  Gene-targeted mice for neighboring genes, including Mtap, Cdkn2a, p19Arf, and Cdkn2b, were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm(2) per section [mean±SD]; P=0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles and CD4(+) cell counts. The Cdkn2a knockout mice had smaller lesions compared with wild-type and heterozygous mice, and there were no significant differences in lesion size in p19Arf and Cdkn2b mutants compared with wild type. We observed extensive, tissue-specific compensatory regulation of the Cdkn2a and Cdkn2b genes among the various knockout mice, making the effects on atherosclerosis difficult to interpret.
  
  
  CONCLUSIONS
  Mtap plays a protective role against atherosclerosis, whereas Cdkn2a appears to be modestly proatherogenic. However, no relation was found between the 9p21 genotype and the transcription of 9p21 neighboring genes in primary human aortic vascular cells in vitro. There is extensive compensatory regulation in the highly conserved 9p21 orthologous region in mice.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1679, USA.
authors.forename: Juyong Brian
authors.initials: JB
authors.lastname: Kim
authors.forename: Andres
authors.initials: A
authors.lastname: Deluna
authors.forename: Imran N
authors.initials: IN
authors.lastname: Mungrue
authors.forename: Christine
authors.initials: C
authors.lastname: Vu
authors.forename: Delila
authors.initials: D
authors.lastname: Pouldar
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.forename: Luz
authors.initials: L
authors.lastname: Orozco
authors.forename: Judy
authors.initials: J
authors.lastname: Wu
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.forename: Sarada
authors.initials: S
authors.lastname: Charugundla
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.forename: Marta
authors.initials: M
authors.lastname: Rusek
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakobowski
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008869:Microtubule-Associated Proteins