Abstract 16964: Integration of Whole Genome Methylation with Metabolomics Identifies Novel Cardiovascular Disease Genes
Background. The genetic architecture underlying the heritability of cardiovascular disease (CVD) is incompletely understood. “Omic” profiling may help elucidate novel biomarkers and disease mechanisms. We have previously identified metabolic signatures associated with CVD. In this study, we hypothesized that epigenetic changes would be present in individuals representing extremes of these signatures, thus identifying novel CVD genes.
Methods. We selected individuals from the Duke CATHGEN study representing the 15 highest and 15 lowest levels of each of two metabolomic factors (short chain dicarboxylacylcarnitine [SCDA] and branched chain amino acid [BCAA] factors), previously shown to be associated with CVD. The Illumina 450K methylation chip was used for whole genome profiling. Differentially methylated probes were identified by a Wilcoxon rank sum test between “extremes” and correlated to the Illumina manifest to identify probe location relative to gene coordinates.
Results. Probes from several genes were differentially methylated (p-value associated with ±10% difference in level of methylation <0.05) in BCAA extremes, including 3 differentially methylated probes spanning an intragenic region from intron 1 to intron 8 of the PAX8 long isoform (p=0.0005-0.0008). When analyzed in the context of epigenetic features within the UCSC genome browser, this region contains a CpG island and shore, H3K27Ac ENCODE region and enriched regions for DNAse hypersensitivity and transcription factor binding sites, indicating the likely regulatory importance of the interval. Probes in several genes were also differentially methylated in SCDA extremes, including periaxin (PRX, p=0.000005) and PTGDR (prostaglandin D2 receptor, p=0.0007).
Conclusions. Integrating metabolomics and epigenetics, we found differential methylation of several genes in individuals representing the extremes of metabolic signatures associated with CVD. PAX8 expression plays a role in endoplasmic reticulum (ER) stress in the thyroid and PAX8 knockout mice display significant cardiac phenotypes. In conjunction with our other work, these results support the role of ER stress response pathways in CVD pathogenesis operating through metabolic variation.
- © 2012 by American Heart Association, Inc.