Authors:
Deepak Voora, MD, Derek Cyr, PhD, Joseph Lucas, PhD, Jen-Tsan Chi, MD, PhD, Jennifer Dungan, PhD, Timothy A. McCaffrey, PhD, Richard Katz, MD, L. Kristin Newby, MD, MHS, William E. Kraus, MD, Richard C. Becker, MD, Thomas L. Ortel, MD PhD, & Geoffrey S. Ginsburg, MD PhD
Summary:
Objectives - To develop RNA profiles that could serve as novel biomarkers for the response to aspirin. Background: Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events.
Methods - We administered aspirin, followed by whole blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1,n=50), and two validation cohorts of volunteers (HV2,n=53) or outpatient cardiology patients (OPC, n=25). Platelet function was assessed by platelet function score (PFS; HV1/HV2) or VerifyNow Aspirin (OPC). Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for association with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death/MI in two patient cohorts (n=587, total) from RNA samples collected at cardiac catheterization.
Results - A set of 60 co-expressed genes named the “aspirin response signature” (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for 17 ARS genes were identified in the platelet proteome, of which, six were associated with PFS. The ARS was associated with death/MI in both patient cohorts (odds ratio = 1.2, p = 0.01 and hazard ratio = 1.5, p = 0.001), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31 - 37%, p ≤ 0.0002) was improved by including the ARS or one of its genes, ITGA2B.
Conclusions - RNA profiles of platelet-specific genes are novel biomarkers for identifying those do not response adequately to aspirin and who are at risk for death/MI.
Source:
Journal of the American College of Cardiology; (07/03/13)