This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/10/1671    most recent ATVBAHA.109.189522v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Jarinova, O. Articles by McPherson, R. PubMed PubMed Citation Articles by Jarinova, O. Articles by McPherson, R. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Coronary Artery Disease

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1671.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus

Olga Jarinova; Alexandre F.R. Stewart; Robert Roberts; George Wells; Paulina Lau; Thet Naing; Christine Buerki; Bradley W. McLean; Richard C. Cook; Joel S. Parker; Ruth McPherson

From the University of Ottawa Heart Institute (O.J., A.F.R.S., R.R., G.W., P.L., T.N., R.M.), Ottawa, Canada; Med BioGene Inc (C.B., B.W.M., R.C.C.), Vancouver, Canada; University of British Columbia (R.C.C.), Vancouver, Canada; and Expression Analysis (J.S.P.), Durham, NC.

Correspondence to Ruth McPherson, Heart Institute, 40 Ruskin St - H441, Ottawa, Canada K1Y 4W7. E-mail rmcpherson{at}ottawaheart.ca

Objectives— We have investigated the functional significance of conserved sequences within the 9p21.3 risk locus for coronary artery disease (CAD) and determined the relationship of 9p21.3 to expression of ANRIL and to whole genome gene expression.

Methods and Results— We demonstrate that a conserved sequence within the 9p21.3 locus has enhancer activity and that the risk variant significantly increases reporter gene expression in primary aortic smooth muscle cells. Whole blood RNA expression of the short variants of ANRIL was increased by 2.2-fold whereas expression of the long ANRIL variant was decreased by 1.2-fold in healthy subjects homozygous for the risk allele. Expression levels of the long and short ANRIL variants were positively correlated with that of the cyclin-dependent kinase inhibitor, CDKN2B (p15) and TDGF1 (Cripto), respectively. Relevant to atherosclerosis, genome-wide expression profiling demonstrated upregulation of gene sets modulating cellular proliferation in carriers of the risk allele.

Conclusion— These findings are consistent with the hypothesis that the 9p21.3 risk allele contains a functional enhancer, the activity of which is altered in carriers of the risk allele. 9p21.3 may promote atherosclerosis by regulating expression of ANRIL, which in turn is associated with altered expression of genes controlling cellular proliferation pathways.

Key Words: coronary artery disease • atherosclerosis • 9p21.3 • noncoding RNA • ANRIL • cellular proliferation