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Digital PCR for Quantifying Circulating MicroRNAs in Acute Myocardial Infarction and Cardiovascular Disease
Published on: July 3, 2018
Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death
Jinhee Kim1, Nima Ghasemzadeh2, Danny J Eapen2
1Center for Integrative Genomics and School of Biology, Georgia Institute of Technology, Boggs Building 1-96, 770 State Street, Atlanta, GA 30332, USA.
Insights
Peripheral blood gene expression profiles can predict cardiovascular death risk in coronary artery disease (CAD) patients. This finding may improve risk stratification beyond traditional methods for adverse cardiovascular events.
Area of Science:
- Cardiovascular Genomics
- Molecular Diagnostics
- Translational Medicine
Background:
- Genetic risk scores for coronary artery disease (CAD) lack predictive power for adverse cardiovascular events.
- Peripheral blood expression profiles are being investigated as potential predictors of cardiovascular outcomes.
Purpose of the Study:
- To determine if peripheral blood gene expression profiles can predict acute myocardial infarction (AMI) and/or cardiovascular death.
- To identify a transcriptional signature associated with cardiovascular mortality in CAD patients.
Main Methods:
- Peripheral blood samples from 338 CAD subjects were analyzed in discovery (N=175) and replication (N=163) phases.
- Gene expression was measured using Illumina HT-12 microarrays; whole genome genotyping supported expression quantitative trait loci analysis.
- Analysis of variance, receiver operating curve, and survival analysis were used to define a cardiovascular death risk signature.
Main Results:
- Significant differential gene expression was observed between healthy and AMI groups, with altered T-lymphocyte signaling and inflammatory gene expression.
- A principal component (PC1) score from 238 differentially expressed genes predicted cardiovascular death risk (HR=8.5, P<0.0001) and improved model discrimination (AUC 0.82 to 0.91).
- Expression quantitative trait loci analysis indicated altered local genetic regulation of transcript abundance in AMI samples.
Conclusions:
- A specific peripheral blood gene expression profile is associated with significant mortality risk in Caucasian CAD subjects.
- This profile includes transcripts also altered during acute myocardial infarction.
- Blood-based gene expression signatures may offer novel avenues for cardiovascular risk assessment.
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 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.
Conclusions:
A 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.
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