Aspirin Exposure Reveals Novel Genes Associated With Platelet Function and Cardiovascular Events

• Published in: Journal of the American College of Cardiology Vol. 62; no. 14; pp. 1267 - 1276
• Main Authors: Voora, Deepak, MD, Cyr, Derek, PhD, Lucas, Joseph, PhD, Chi, Jen-Tsan, MD, PhD, Dungan, Jennifer, PhD, McCaffrey, Timothy A., PhD, Katz, Richard, MD, Newby, L. Kristin, MD, MHS, Kraus, William E., MD, Becker, Richard C., MD, Ortel, Thomas L., MD, PhD, Ginsburg, Geoffrey S., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-2013; Elsevier; Elsevier Limited
• Subjects: Aspirin; Aspirin - therapeutic use; Bayes Theorem; Biological and medical sciences; Biomarkers; Blood platelets; Blood Platelets - drug effects; Blood Platelets - physiology; Bones, joints and connective tissue. Antiinflammatory agents; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cardiovascular Diseases - blood; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - genetics; Cell division; Chromosomes; Confidence intervals; Family medical history; Gene expression; genes; Genes - drug effects; Genes - genetics; Heart; Humans; Internal Medicine; Intubation; Kinases; Mass spectrometry; Medical sciences; Microarray Analysis; Mortality; myocardial infarction; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - therapeutic use; Platelet Function Tests; platelets; Proteins; Proteomics - methods; Quality control; Real-Time Polymerase Chain Reaction; Risk Factors; RNA - analysis; United States > US; California; coronary artery disease; ARS; ribonucleic acid; OPC; RNA; platelet function score; myocardial infarction; Catheterization Genetics; DUMC; healthy volunteer validation cohort; outpatient cardiology cohort; odds ratio; MPV; RT-PCR; aspirin; MI; PFS; polymerase chain reaction; Duke University Medical Center; HV1; OR; healthy volunteer discovery cohort; genes; HV2; biomarkers; CI; CAD; real-time polymerase chain reaction; platelets; CATHGEN; aspirin response signature; confidence interval; PCR; mean platelet volume; Prostaglandin-endoperoxide synthase; Enzyme; Enzyme inhibitor; Cardiovascular disease; Exposure; Acetylsalicylic acid; Antiplatelet agent; Non steroidal antiinflammatory agent; Analgesic; Association; Gene; Platelet function; Antipyretic; Genetics; Oxidoreductases; Salicylates; Circulatory system; Cardiology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2013.05.073

Objectives The aim of this study was to develop ribonucleic acid (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 Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations 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 or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. Results A set of 60 coexpressed 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 the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. Conclusions RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI.