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Researchers Identify Gene Expression Signature Linked to Cardiovascular Death Risk

NEW YORK (GenomeWeb) — Researchers have uncovered a gene expression signature linked to risk of cardiovascular death, as they reported last night in Genome Medicine.

Researchers led by Gregory Gibson, director of the Center for Integrative Genomics at Georgia Tech, examined gene expression profiles in some 338 patients with coronary artery disease. During the course of follow up, 31 of those patients died from the disease. By comparing the gene expression profiles of those two groups, Gibson and his colleagues teased out an expression signature based on some 230 genes marked by the upregulation of inflammatory genes and the downregulation of T-lymphocyte genes that are linked to cardiovascular death risk.

"We envision that with our gene expression-based marker, plus some biochemical markers, genotype information, and family history, we could produce a tiered evaluation of people's risks of adverse coronary events," Gibson said in a statement. "This could lead to a personalized medicine approach for people recovering from heart attack or coronary artery bypass grafting."

In the United States, coronary artery disease is the leading cause of death, but the researchers noted that genetic risk scores developed for CAD and atherosclerosis aren't predictive of adverse cardiovascular events like heart attacks or death.

For their study, Gibson and his colleagues enrolled some 338 patients with suspected or confirmed cardiovascular disease who were undergoing cardiac catheterization. They divvied this population into those with non-significant CAD or significant CAD, and by whether or not they'd had an acute myocardial infarction upon admission or a past history of myocardial infarction. Of these, 175 patients made up the discovery cohort and 163 were in the replication cohort.

Using an Illumina HT-12 bead array and analyzing some 14,100 probes, the researchers found that the expression of up to 4,500 transcripts varied between whether the participants were classified as having non-significant CAD, significant CAD, acute myocardial infarction, or history of myocardial infarction. The researchers used two normalization protocols — the SNM algorithm and linear mixed modeling— to account for technical and biological variation.

For the discovery and replication phases, Gibson and his colleagues reported a signature linked to acute myocardial infarction that was enriched for the upregulation of neutrophil-related genes and the downregulation of T-lymphocyte genes. They noted, though, that not all neutrophil- and T-lymphocyte-related transcripts were affected to the same degree.

Additionally, eQTL analysis of the discovery cohort indicated that there was altered local genetic regulation of transcript levels in acute myocardial infarction patients.

After a mean 2.4 years of follow up, 31 patients from the combined cohort died of cardiovascular causes — 23 from the discovery and eight from the replication cohort. By comparing their gene expression profiles to the other patients in the cohort, the researchers homed in on 238 genes whose expression varied between the groups.

This PC1 score was predictive of cardiovascular death in the discovery cohort and confirmed in the replication cohort. Additionally, the hazard ratio of the PC1 score indicated a more than eight-fold increased risk of death.

According to the researchers, the genes making up this signature are involved in a number of processes, including gylcerophospholipid metabolism and sphingomyelin-mediated signaling, thrombosis, leukocyte recruitment, and PI3K-Akt signaling, as well as a number of genes that are upregulated in CD133+ hematopoietic stem cells.

The score is also correlated with upregulation of neutrophil-related genes and the downregulation of T-lymphocyte, indicating that a subset of the genes linked to acute myocardial infarction are also linked to cardiovascular death.

"Our results suggest that there may be a specific subset of leukocyte gene activity that is associated with a particularly high risk of death among individuals with CAD," the researchers said in their paper.

However, the researchers noted that there is no known mechanism that links the signature to risk of death, something, they added, that would be helpful to know to move the signature into clinical practice.

"If independently validated, a peripheral blood transcript abundance test has potential, in conjunction with measures of cholesterol, serum creatinine, and white blood cell counts, to generate a significant predictor of risk of cardiovascular death in patients with CAD," they added.