Abstract 11549: Genetic Variants in the Locus 9p21 Contribute to Atherosclerosis Through Modulation of ANRIL and CDKN2A/B
Introduction: GWAS have identified genetic variants contributing to the risk of coronary artery disease (CAD) in the chromosome 9p21 locus. The CAD associated region is laying on the surroundings of two cyclin dependent kinase inhibitors (CDKN) 2A and 2B and the last exons of a non-coding RNA ANRIL. CDKN2A/B established role in cell proliferation and senescence make them appealing candidates to mediate these associations but it is still not clear which or how these transcripts are involved in the pathogenesis of atherosclerosis.
Hypothesis: We assess the hypothesis that the 9p21locus polymorphisms influence the expression of the transcripts in the region (ANRIL, CDKN2A/B) and these transcripts contribute to atherogenesis through modulation of proliferation.
Methods: We genotyped 18 selected SNPs (r2<0.8 and MAF>0.05) across the region of interest: CDKN2A/B and ANRIL, encompassing the CAD-associated region. RNA and DNA were extracted from blood of 57 volunteers (69-72 years old). Carotid ultrasound was performed in all subjects. CDKN2A/B and ANRIL (exons 1-2 and 18-19) expression was measured by RT-PCR. Gene expression and proliferation were evaluated in cultured VSMC after siRNA mediated knock-down of ANRIL.
Results: The risk alleles for atherosclerosis-related phenotypes were consistently associated with a lower expression of ANRIL when evaluating the 1-2 exons. Common carotid artery stenosis was associated with a significantly lower (p<0.01) expression of ANRIL (exon 1-2). ANRIL knock-down in VSMC caused significant variation in expression of CDKN2A/B (p<0.05) and cell proliferation reduction (p<0.05) in vitro.
Conclusion: Disease-associated SNPs in the locus 9p21 affect predominantly the expression of ANRIL. Our results altogether point at a probable important role of ANRIL in the progression of human atherosclerosis via the regulation of CDKN2A/B and proliferation.
- © 2011 by American Heart Association, Inc.