Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Jarinova
Olga
O
University of Ottawa Heart Institute, Ottawa, Canada.
Stewart
Alexandre F R
AF
Roberts
Robert
R
Wells
George
G
Lau
Paulina
P
Naing
Thet
T
Buerki
Christine
C
McLean
Bradley W
BW
Cook
Richard C
RC
Parker
Joel S
JS
McPherson
Ruth
R
D000368:Aged; D000483:Alleles; D050197:Atherosclerosis / Q000235:genetics; D049109:Cell Proliferation; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003324:Coronary Artery Disease / Q000209:etiology / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics / Q000502:physiology; D050436:Regulatory Elements, Transcriptional; D012306:Risk
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D022661:RNA, Untranslated; C070636:TDGF1 protein, human; D004815:Epidermal Growth Factor; D008156:Luciferases