Abstract
BackgroundGenetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events. We asked whether peripheral blood expression profiles may be predictive of acute myocardial infarction (AMI) and/or cardiovascular death.MethodsPeripheral blood samples from 338 subjects aged 62 ± 11 years with coronary artery disease (CAD) were analyzed in two phases (discovery N = 175, and replication N = 163), and followed for a mean 2.4 years for cardiovascular death. Gene expression was measured on Illumina HT-12 microarrays with two different normalization procedures to control technical and biological covariates. Whole genome genotyping was used to support comparative genome-wide association studies of gene expression. Analysis of variance was combined with receiver operating curve and survival analysis to define a transcriptional signature of cardiovascular death.ResultsIn both phases, there was significant differential expression between healthy and AMI groups with overall down-regulation of genes involved in T-lymphocyte signaling and up-regulation of inflammatory genes. Expression quantitative trait loci analysis provided evidence for altered local genetic regulation of transcript abundance in AMI samples. On follow-up there were 31 cardiovascular deaths. A principal component (PC1) score capturing covariance of 238 genes that were differentially expressed between deceased and survivors in the discovery phase significantly predicted risk of cardiovascular death in the replication and combined samples (hazard ratio = 8.5, P < 0.0001) and improved the C-statistic (area under the curve 0.82 to 0.91, P = 0.03) after adjustment for traditional covariates.ConclusionsA specific blood gene expression profile is associated with a significant risk of death in Caucasian subjects with CAD. This comprises a subset of transcripts that are also altered in expression during acute myocardial infarction.
Highlights
Genetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events
One small study of 28 cases [13] documented a peripheral blood gene expression signature associated with acute myocardial infarction (AMI) that persisted to some extent on follow-up
Differential expression associated with acute myocardial infarction Exploratory analyses indicated that as many as 4,500 transcripts may differ in abundance with respect to their Coronary artery disease (CAD) status, namely NO CAD, CAD, OLD MI, or AMI
Summary
Genetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events. We asked whether peripheral blood expression profiles may be predictive of acute myocardial infarction (AMI) and/or cardiovascular death. One small study of 28 cases [13] documented a peripheral blood gene expression signature associated with acute myocardial infarction (AMI) that persisted to some extent on follow-up. It is not clear whether this signature is broadly predictive of risk or represents perturbation during the event. A distinct subset of these generate a predictor of future cardiovascular death that replicates in two phases of analysis and is strongly associated with survival time in the combined dataset
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