Ken Sugimoto
   Department   Kawasaki Medical School  Kawasaki Medical School, Department of General Geriatric Medicine,
   Position   Professor
Article types 原著
Language English
Peer review Peer reviewed
Title Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B.
Journal Formal name：Atherosclerosis
Abbreviation：Atherosclerosis
ISSN code：18791484/00219150
Domestic / ForeginForegin
Volume, Issue, Page 220(2),pp.449-455
Author and coauthor Congrains Ada, Kamide Kei, Oguro Ryousuke, Yasuda Osamu, Miyata Keishi, Yamamoto Eiichiro, Kawai Tatsuo, Kusunoki Hiroshi, Yamamoto Hiroko, Takeya Yasushi, Yamamoto Koichi, Onishi Miyuki, Sugimoto Ken, Katsuya Tomohiro, Awata Nobuhisa, Ikebe Kazunori, Gondo Yasuyuki, Oike Yuichi, Ohishi Mitsuru, Rakugi Hiromi
Publication date 2012/02
Summary UNLABELLED: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 (69-72 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.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.
DOI 10.1016/j.atherosclerosis.2011.11.017
PMID 22178423