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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.

Methylation of p15INK4b and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease