Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus.
Arterioscler Thromb Vasc Biol
; 29(10): 1671-7, 2009 Oct.
Article
em En
| MEDLINE
| ID: mdl-19592466
ABSTRACT
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. METHODS ANDRESULTS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cromossomos Humanos Par 9
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Doença da Artéria Coronariana
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Mapeamento Cromossômico
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Aged
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Female
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Humans
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Male
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Canadá