INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis

Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated wh...

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Bibliographic Details
Published in:	PloS one 2009-04, Vol.4 (4), p.e5027-e5027
Main Authors:	Liu, Yan, Sanoff, Hanna K, Cho, Hyunsoon, Burd, Christin E, Torrice, Chad, Mohlke, Karen L, Ibrahim, Joseph G, Thomas, Nancy E, Sharpless, Norman E
Format:	Article
Language:	eng
Subjects:	Aging Analysis Aneurysms Aorta Arteriosclerosis Atherosclerosis Atherosclerosis - genetics Cancer Cardiovascular disease Cardiovascular Disorders/Coronary Artery Disease Cell Biology/Cell Growth and Division Cell cycle Cell growth Chromosome 9 Chromosomes Chromosomes, Human, Pair 9 Coronary artery Coronary artery disease Coronary heart disease Cyclin-Dependent Kinase Inhibitor Proteins - genetics Cyclin-dependent kinase inhibitors Diabetes mellitus Gene expression Genetic aspects Genetics Genetics and Genomics/Gene Expression Genome-wide association studies Genome-Wide Association Study Genomes Genotype Genotypes Haplotypes Health risks Heart diseases Humans INK4 protein INK4a protein Loci Lymphocytes T Medicine Multivariate analysis Oxidative stress p16 Protein Peripheral blood Polymorphism, Single Nucleotide Proteins Risk RNA, Messenger - genetics Senescence Single nucleotide polymorphisms Single-nucleotide polymorphism Smooth muscle Stem cells T cells Telomerase Transcription Trends Tumor suppressor genes Type 2 diabetes Values
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Summary:	Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a), p15(INK4b), ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs. We analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15(INK4b), p16(INK4a), ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs. Genotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.
ISSN:	1932-6203 1932-6203