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

被引：276

作者：

Congrains, Ada ^{[1
]}

Kamide, Kei ^{[1
]}

Oguro, Ryousuke ^{[1
]}

Yasuda, Osamu ^{[2
]}

Miyata, Keishi ^{[3
]}

Yamamoto, Eiichiro

Kawai, Tatsuo ^{[1
]}

Kusunoki, Hiroshi

Yamamoto, Hiroko ^{[1
]}

Takeya, Yasushi ^{[1
]}

Yamamoto, Koichi ^{[1
]}

Onishi, Miyuki ^{[1
]}

Sugimoto, Ken ^{[1
]}

Katsuya, Tomohiro

Awata, Nobuhisa ^{[4
]}

Ikebe, Kazunori ^{[5
]}

Gondo, Yasuyuki ^{[6
]}

Oike, Yuichi ^{[3
]}

Ohishi, Mitsuru ^{[1
]}

Rakugi, Hiromi ^{[1
]}

机构：

[1] Osaka Univ, Dept Geriatr Med & Nephrol, Grad Sch Med, Suita, Osaka 5650871, Japan

[2] Kumamoto Univ Hosp, Dept Cardiovasc Clin & Translat Res, Kumamoto, Japan

[3] Kumamoto Univ, Dept Mol Genet, Grad Sch Med Sci, Kumamoto 860, Japan

[4] Osaka Med Ctr Canc & Cardiovasc Dis, Dept Cardiol, Osaka, Japan

[5] Osaka Univ, Dept Prosthodont & Oral Rehabil, Sch Dent, Suita, Osaka 5650871, Japan

[6] Osaka Univ, Dept Clin Thanatol & Geriatr Behav Sci, Grad Sch Human Sci, Suita, Osaka 5650871, Japan

来源：

ATHEROSCLEROSIS | 2012年 / 220卷 / 02期

关键词：

Chromosome; 9p21; ANRIL; CDKN2A; CDKN2B; Atherosclerosis; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; CHROMOSOME; 9P21.3; MYOCARDIAL-INFARCTION; NONCODING RNA; RISK; SUSCEPTIBILITY; EXPRESSION; MELANOMA; DELETION;

D O I：

10.1016/j.atherosclerosis.2011.11.017

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

引用

页码：449 / 455

页数：7

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