Portal de Periódicos da CAPES

Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B

2011; Elsevier BV; Volume: 220; Issue: 2 Linguagem: Inglês

10.1016/j.atherosclerosis.2011.11.017

1879-1484

Ada Congrains, Kei Kamide, Ryousuke Oguro, Osamu Yasuda, Keishi Miyata, Eiichiro Yamamoto, Tatsuo Kawai, Hiroshi Kusunoki, Hiroko Yamamoto, Yasushi Takeya, Kōichi Yamamoto, Miyuki Onishi, Ken Sugimoto, Tomohiro Katsuya, Nobuhisa Awata, Kazunori Ikebe, Yasuyuki Gondo, Yuichi Oike, Mitsuru Ohishi, Hiromi Rakugi,

Galectins and Cancer Biology

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.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.We genotyped 18 SNPs (r(2) 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 (69-72 years 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.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.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.