Abstract 16260: Aspirin-Responsive Platelet Genes Are Associated With Platelet Function and Cardiovascular Events

Abstract

Background: Aspirin prevents myocardial infarction (MI); the pathways with which aspirin interacts are not fully described. We hypothesized that genes that changed in response to aspirin exposure would be associated with platelet function and death/MI. Methods: Discovery (healthy volunteers; n=53) and Validation (diabetic patients; n=45) cohorts were exposed to aspirin 325mg/day. Before and after aspirin exposure, we measured platelet function by aggregometry and gene/platelet protein expression by whole blood RNA microarray analysis and unbiased proteomics of purified platelet protein, respectively. Gene Set Enrichment Analysis (GSEA) identified gene sets that changed in response to aspirin. Paired t-tests and regression were used to test individual genes and proteins for changes in expression with aspirin or association with platelet function, respectively. Cox regression models tested gene sets in aggregate using the 1st principal component of gene expression for association with death/MI in patients (n =638) using RNA collected at cardiac catheterization. Results: In the discovery cohort we identified 25 gene sets that changed in response to aspirin (family wise error rate [FWER] < 0.05). Of these, we chose to follow up on one set of 43 genes because it represented abundant platelet genes. This gene set was down regulated in the discovery and validation cohorts (FWER p = 0.01 and 0.04, respectively). We identified 4 of 43 genes in the platelet protein dataset; the expression of 3 changed (p < 0.03) in response to aspirin and was associated (p < 0.01) with platelet function after accounting for aspirin. The aggregate expression of this platelet gene set was associated with death/MI (p = 0.03) with the majority of genes associated with increased risk. Analysis of individual genes in this gene set identified several (HLA-E, H3F3A, GNAS, FTH1, TUBA4A, OAZ1, FLNA) that were significantly (p < 0.05) down-regulated by aspirin and also associated with an increased risk of death/MI. Conclusion: By using aspirin as a probe to uncover novel biology we identified a set of aspirin-responsive platelet genes associated with an increased risk of cardiovascular events. These findings may help to explain the effects of aspirin on preventing MI.