Biomaterial Database

Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells. 2012

Anna Motterle, and Xiangyuan Pu, and Harriet Wood, and Qingzhong Xiao, and Shivani Gor, and Fu Liang Ng, and Kenneth Chan, and Frank Cross, and Beski Shohreh, and Robin N Poston, and Arthur T Tucker, and Mark J Caulfield, and Shu Ye

Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.

Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.

UI	MeSH Term	Description	Entries
D009131	Muscle, Smooth, Vascular	The nonstriated involuntary muscle tissue of blood vessels.	Vascular Smooth Muscle,Muscle, Vascular Smooth,Muscles, Vascular Smooth,Smooth Muscle, Vascular,Smooth Muscles, Vascular,Vascular Smooth Muscles
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002899	Chromosomes, Human, Pair 9	A specific pair of GROUP C CHROMSOMES of the human chromosome classification.	Chromosome 9
D003324	Coronary Artery Disease	Pathological processes of CORONARY ARTERIES that may derive from a congenital abnormality, atherosclerotic, or non-atherosclerotic cause.	Arteriosclerosis, Coronary,Atherosclerosis, Coronary,Coronary Arteriosclerosis,Coronary Atherosclerosis,Left Main Coronary Artery Disease,Left Main Coronary Disease,Left Main Disease,Arterioscleroses, Coronary,Artery Disease, Coronary,Artery Diseases, Coronary,Atheroscleroses, Coronary,Coronary Arterioscleroses,Coronary Artery Diseases,Coronary Atheroscleroses,Left Main Diseases
D005838	Genotype	The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.	Genogroup,Genogroups,Genotypes
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015870	Gene Expression	The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.	Expression, Gene,Expressions, Gene,Gene Expressions
D049109	Cell Proliferation	All of the processes involved in increasing CELL NUMBER including CELL DIVISION.	Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D050197	Atherosclerosis	A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA.	Atherogenesis,Atherogeneses,Atheroscleroses
D050762	Cyclin-Dependent Kinase Inhibitor p15	An INK4 cyclin-dependent kinase inhibitor containing four ANKYRIN-LIKE REPEATS. INK4B is often inactivated by deletions, mutations, or hypermethylation in HEMATOLOGIC NEOPLASMS.	CDKN2B Protein,Cyclin-Dependent Kinase Inhibitor 2B,INK4B Protein,INK4b Cyclin-Dependent Kinase Inhibitor,p15 CDK4 Inhibitor,p15INK4B Protein,CDK4 Inhibitor, p15,Cyclin Dependent Kinase Inhibitor 2B,Cyclin Dependent Kinase Inhibitor p15,INK4b Cyclin Dependent Kinase Inhibitor