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Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease

BACKGROUND: Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The methylat...

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Autores principales: Zhuang, Jianhui, Peng, Wenhui, Li, Hailing, Wang, Wei, Wei, Yidong, Li, Weiming, Xu, Yawei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473029/
https://www.ncbi.nlm.nih.gov/pubmed/23091611
http://dx.doi.org/10.1371/journal.pone.0047193
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author Zhuang, Jianhui
Peng, Wenhui
Li, Hailing
Wang, Wei
Wei, Yidong
Li, Weiming
Xu, Yawei
author_facet Zhuang, Jianhui
Peng, Wenhui
Li, Hailing
Wang, Wei
Wei, Yidong
Li, Weiming
Xu, Yawei
author_sort Zhuang, Jianhui
collection PubMed
description BACKGROUND: Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14(ARF), p15(INK4b) and p16(INK4a)) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15(INK4b) significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15(INK4b), pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15(INK4b) hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1–5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15(INK4b) and p16(INK4a) methylation as ANRIL exon 1–5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype. CONCLUSIONS/SIGNIFICANCE: p15(INK4b) methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15(INK4b) methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development.
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spelling pubmed-34730292012-10-22 Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease Zhuang, Jianhui Peng, Wenhui Li, Hailing Wang, Wei Wei, Yidong Li, Weiming Xu, Yawei PLoS One Research Article BACKGROUND: Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14(ARF), p15(INK4b) and p16(INK4a)) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15(INK4b) significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15(INK4b), pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15(INK4b) hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1–5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15(INK4b) and p16(INK4a) methylation as ANRIL exon 1–5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype. CONCLUSIONS/SIGNIFICANCE: p15(INK4b) methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15(INK4b) methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development. Public Library of Science 2012-10-16 /pmc/articles/PMC3473029/ /pubmed/23091611 http://dx.doi.org/10.1371/journal.pone.0047193 Text en © 2012 Zhuang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhuang, Jianhui
Peng, Wenhui
Li, Hailing
Wang, Wei
Wei, Yidong
Li, Weiming
Xu, Yawei
Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title_full Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title_fullStr Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title_full_unstemmed Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title_short Methylation of p15(INK4b) and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease
title_sort methylation of p15(ink4b) and expression of anril on chromosome 9p21 are associated with coronary artery disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473029/
https://www.ncbi.nlm.nih.gov/pubmed/23091611
http://dx.doi.org/10.1371/journal.pone.0047193
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