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

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.

Autosomal genetic control of human gene expression does not differ across the sexes

“…The Coronary Artery Disease (CAD) cohort comprised 147 unrelated individuals enrolled in the Emory Cardiovascular Biobank, USA, with suspected or confirmed CAD [32]. RNA was collected from whole-blood samples with expression levels measured in 47,231 genome-wide probes using the Illumina HumanHT-12 Beadchip.…”

The effect of X-linked dosage compensation on complex trait variation

“…Gene expression and X-chromosome genotype data were available in a subset of N=2,130 individuals (N=1,084 males, N=1,046 females) from the Consortium for the Architecture of Gene Expression (CAGE), a study examining the genetic architecture of gene expression in a mixture of pedigree and unrelated individuals (Lloyd-jones et al, 2017). This subset of individuals comes from three cohorts with genotype data on the X chromosome (Powell et al, 2012(Powell et al, , 2013Kim et al, 2014;Leitsalu et al, 2015), and are of European ancestry, as identified by principal component analysis with the HapMap3 populations. Further details are provided in (Lloyd-jones et al, 2017).…”

Genome-Wide Significant Loci: How Important Are They?

“…Because of their rapid turnover, tissue protein profiles (as opposed to RNA expression) are more variable, and it is now appreciated that protein, metabolite, and lipid analyses are not as well-suited for systems analyses at the genome-wide level in individual human tissues, given the current state of the technology to measure these different dimensions. However, patterns of protein and metabolite expression in plasma may be an exception (73,74), and integrating RNA expression with protein and metabolite profiles can greatly enhance the predictive power of disease gene networks (75). …”