Abstract 13189: Association of DNA Methylation and Gene Expression of the P2Y12 Receptor: The Multi-Ethnic Study on Atherosclerosis
Background: P2Y12 receptor is the target for thienopyridine mediated platelet inhibition. Epigenetic factors, including DNA methylation could influence gene expression and subsequent in vitro and clinical response to thienopyridine therapy. Our aim was to determine the relationships between DNA methylation at cis acting CpG sites and P2RY12 gene expression.
Methods: 1264 MESA participants (590 White, 272 Black, 402 Hispanic) underwent methylomic and transcriptional profiling of monocytes using Illumina HumanMethylation450 BeadChip and HumanHT-12 v4 Expression BeadChip respectively. Data were adjusted for chip, chip position, age, gender, race, MESA site and contamination with non-monocytes. Univariate regression was performed between the 59 methylation loci within 500KB of the P2RY12 gene and gene expression levels. Multiple linear regression with backwards elimination procedure was used to identify a subset of the 59 markers (CpG sites) independently contributing to prediction of gene expression.
Results: Of the 59 loci, 11 were nominally significantly associated with gene expression in univariate analyses (table). Multiple linear regression identified 12 loci significantly associated with gene expression at the p=0.05 level with an overall model r2 of 0.12 and an adjusted model p=3.06x10-24. The 3 most significant CpG loci were located in the first intron, last intron, and 25KB 5’ to the P2RY12 gene respectively. In race/ethnicity stratified analyses, different loci were significant in each race/ethnic group, though all models had r2 values of 0.08-0.15.
Conclusion: Variation in degree of methylation at numerous CpG sites in the vicinity of the P2RY12 gene were associated with P2Ry12 mRNA expression. Association between individual CpG loci and expression varied by race/ethnic group. Further studies are needed to determine whether methylation at these sites significantly influences platelet function or clinical responses to thienopyridines.
- © 2013 by American Heart Association, Inc.