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Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B
- Source :
-
Atherosclerosis (00219150) . Feb2012, Vol. 220 Issue 2, p449-455. 7p. - Publication Year :
- 2012
-
Abstract
- Abstract: Genome-wide association studies (GWAS) have identified genetic variants contributing to the risk of cardiovascular disease (CVD) at the chromosome 9p21 locus. The CVD-associated region is adjacent to the two cyclin dependent kinase inhibitors (CDKN)2A and 2B and the last exons of the non-coding RNA, ANRIL. It is still not clear which of or how these transcripts are involved in the pathogenesis of atherosclerosis. Objective: We assessed the hypothesis that 9p21 locus polymorphisms influence the expression of the transcripts in the region (ANRIL, CDKN2A/B) and that these transcripts contribute to atherogenesis through the modulation of proliferation in VSMC. Methods: We genotyped 18 SNPs (r 2 <0.8 and MAF>0.05) across the region of interest: CDKN2A/B and ANRIL, encompassing the CVD-associated region. RNA and DNA were extracted from the blood of 57 volunteers (69–72years old). Carotid ultrasound was performed in 56 subjects. CDKN2A/B and ANRIL (exons 1–2 and 17–18) expression was measured employing RT-PCR. Gene expression and cell growth were evaluated in cultured VSMC after the 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 exons 1–2. Common carotid artery stenosis was associated with a significantly lower (P <0.01) expression of ANRIL (exons 1–2). ANRIL knock-down in VSMC caused significant variation in expression of CDKN2A/B (P <0.05) and reduction of cell growth (P <0.05) in vitro. Conclusion: Disease-associated SNPs at the 9p21 locus predominantly affect the expression of ANRIL. Overall, our results suggest that several CVD-associated SNPs in the 9p21 locus affect the expression of ANRIL, which, in turn modulate cell growth, possibly via CDKN2A/B regulation. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 00219150
- Volume :
- 220
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Atherosclerosis (00219150)
- Publication Type :
- Academic Journal
- Accession number :
- 70948818
- Full Text :
- https://doi.org/10.1016/j.atherosclerosis.2011.11.017