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Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease

ABSTRACT: Gene expression profile in circulating leukocytes identifies patients with coronary artery disease Peter Sinnaeve, Mark Donahue, Peter Grass, Jacky Vonderscher, David Seo, Pascal Goldschmidt, Christopher Granger Department of Medicine, Duke University, Durham, NC, USA, Novartis Institute for Biomedical Research, Cambridge, Boston, MA, USA Introduction Systemic and local inflammation plays a prominent pathogenetic role in atherosclerotic coronary artery disease (CAD), but the relationship of phenotypic changes in circulating leukocytes and extent of CAD remains unclear. We have investigated whether gene expression patterns in circulating leukocytes are associated with presence and extent of CAD. Methods Patients undergoing coronary angiography were selected according to their Duke CAD index (CADi), a validated angiographical measure of the extent of coronary atherosclerosis that correlates with outcome. RNA was extracted from 110 patients with CAD (CADi>23) and from 112 partially matched controls without CAD (CADi=0). Gene expression was assessed using Affymetrix U133A chips. Genes correlating with CAD were identified using Spearman’s rank correlation, and predictive gene expression patterns were identified using a partial least squares (PLS) regression analysis. Results 160 individual genes were found to significantly correlate with CADi (rho>0.2, P<0.0027), although changes in individual gene expression were relatively small (1.2 to 1.5 fold). Using these 160 genes, the PLS multivariate regression resulted in a highly predictive model (r2=0.764, P<0.001). Cross-validation showed that most of the predictive model was carried by only 8 genes (r2=0.752) (table 1). Conclusion Simultaneous expression pattern of 8 genes appears to be highly predictive for CAD. Peripheral leukocyte gene expression pattern could be a novel non-invasive biomarker for CAD and lead to new pathophysiologic insights. parallel group design

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PROVIDER: S-DIXA-D-1007 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:AimsNatriuretic peptides are useful for diagnosis and prognostication of heart failure of any cause. Now, research aims to discover novel biomarkers that will more specifically define the heart failure phenotype. DNA methylation plays a critical role in the development of cardiovascular disease with the potential to predict fundamental pathogenic processes. There is a lack of data relating DNA methylation in heart failure that specifically focuses on patients with severe multi-vessel coronary artery disease. To begin to address this, we conducted a pilot study uniquely exploring the utility of powerful whole-genome methyl-binding domain-capture sequencing in a cohort of cardiac surgery patients, matched for the severity of their coronary artery disease, aiming to identify candidate peripheral blood DNA methylation markers of ischaemic cardiomyopathy and heart failure.Methods and resultsWe recruited a cohort of 20 male patients presenting for coronary artery bypass graft surgery with phenotypic extremes of heart failure but who otherwise share a similar coronary ischaemic burden, age, sex, and ethnicity. Methylation profiling in patient blood samples was performed using methyl-binding domain-capture sequencing. Differentially methylated regions were validated using targeted bisulfite sequencing. Gene set enrichment analysis was performed to identify differences in methylation at or near gene promoters in certain known Reactome pathways. We detected 567 188 methylation peaks of which our general linear model identified 68 significantly differentially methylated regions in heart failure with a false discovery rate <0.05. Of these regions, 48 occurred within gene bodies and 25 were located near enhancer elements, some within coding genes and some in non-coding genes. Gene set enrichment analyses identified 103 significantly enriched gene sets (false discovery rate <0.05) in heart failure. Validation analysis of regions with the strongest differential methylation data was performed for two genes: HDAC9 and the uncharacterized miRNA gene MIR3675. Genes of particular interest as novel candidate markers of the heart failure phenotype with reduced methylation were HDAC9, JARID2, and GREM1 and with increased methylation PDSS2.ConclusionsWe demonstrate the utility of methyl-binding domain-capture sequencing to evaluate peripheral blood DNA methylation markers in a cohort of cardiac surgical patients with severe multi-vessel coronary artery disease and phenotypic extremes of heart failure. The differential methylation status of specific coding genes identified are candidates for larger longitudinal studies. We have further demonstrated the value and feasibility of examining DNA methylation during the perioperative period to highlight biological pathways and processes contributing to complex phenotypes.

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Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease

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