Methylation of p15INK4b and Expression of ANRIL on Chromosome 9p21 are Associated with Coronary Artery Disease
Background: Genome-wide association studies have identified that multiple singlenucleiotide polymorphisms on chromosome 9p21 are tightly associated with (coronaryartery disease) CAD. However, the mechanism linking this risk locus to CAD remainsunclear.Methodology/Principal Findings: The methylation status of six candidate genes (BAX,BCL-2, TIMP3, p14ARF, p15INK4b and p16INK4a) in 205 patients and controls who underwentcoronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 wasgenotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus(ANRIL) was determined by real-time RT-PCR. Serum levels of TGF-β1 were measured byELISA. Compared with controls, DNA methylation levels at p15INK4b significantly increasedin CAD patients (P=0.006). To validate and dissect the methylation percentage of each targetCpG site at p15INK4b, Pyrosequencing was performed, finding CpG +314 remarkablyhypermethylated in CAD patients. The rs10757274 genotype was significantly associatedwith CAD (P=0.003) and GG genotype carriers had a higher level of ANRIL exon 1-5expression compared among three genotypes (P=0.009). There was a stepwise increase inp15INK4b and p16INK4a methylation as ANRIL exon 1-5 expression elevated (r=0.23, P=0.001and r=0.24, P=0.001, respectively), although neither of two loci methylation was directlylinked to rs10757274 genotype.Conclusions/Significance: p15INK4b methylation is associated with CAD and ANRILexpression. The epigenetic changes in p15INK4b methylation and ANRIL expression mayinvolve in the mechanisms of chromosome 9p21 on CAD development.
chromosome 9p21, ANRIL, DNA methylation, gene expression, coronaryartery disease
Jianhui Zhuang Wenhui Peng Hailing Li Wei Wang Yidong Wei Weiming Li Yawei Xu
Department of Cardiology,Shanghai Tenth People”s Hospital,Tongji University School of Medicine,Shang Laboratory of Blood and Vascular Biology,The Rockefeller University,New York,United States of Americ
国内会议
2012上海市研究生学术论坛暨第三届上海交通大学医(理)工研究生学术论坛
上海
英文
1-38
2012-08-15（万方平台首次上网日期，不代表论文的发表时间）