Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death

Jinhee Kim, Nima Ghasemzadeh, Danny J Eapen, Neo Christopher Chung, John D Storey,Arshed A Quyyumi and Greg Gibson

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Genome Medicine 2014, 6:40 doi:10.1186/gm560

Published: 30 May 2014

Abstract (provisional)

Background

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.

Methods

Peripheral 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.

Results

In 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 QTL (eQTL) 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 (HR = 8.5, p < 0.0001) and improved the C-statistic (Area Under the Curve: 0.82-0.91, p = 0.03) after adjustment for traditional covariates.

Conclusion

A specific blood gene expression profile is associated with a significant risk of death in Caucasian subjects with CAD. These are a subset of transcripts that are also altered in expression during acute myocardial infarction.