Abstract 18385: Platelet Transcriptome in Type 2 Diabetes Provides Insight Into Peripheral Artery Disease and Cardiovascular Events

Abstract

Background: Platelets are integral to atherothrombosis and peripheral artery disease (PAD), processes that are accelerated in diabetes. We evaluated the platelet transcriptome, generated a platelet RNA score, and investigated whether it could serve as a novel biomarker of PAD severity and major adverse cardiovascular events (MACE). Methods: We performed RNA sequencing on circulating platelet samples obtained from 133 patients enrolled in the platelet activity and cardiovascular events in PAD study. The transcriptome was (1) compared in PAD patients with Type 2 Diabetes (T2D) (n=73) vs without T2D (n=60), and (2) correlated with platelet aggregation responses to submaximal epinephrine (0.4uM). Using the overlap of transcripts identified by these approaches, we scored each sample based on a rank-based phenotypic metric (Singscore) to develop a T2D-specific platelet RNA score. This platelet score was compared in PAD patients with (vs without) critical limb ischemia (CLI), and PAD patients with (vs without) incident MACE (myocardial infarction, stroke, or death) after multivariable adjustment. Results: Overall, 384 transcripts were differentially expressed in PAD patients with vs without T2D (P<0.01; 195 upregulated and 189 downregulated). Gene set enrichment analysis noted upregulation of pathways related to cell chemotaxis, acute inflammatory response, and platelet alpha granules in T2D. Among these 384 genes, 102 significantly correlated with platelet aggregation (P<0.01) and were used to create a T2D platelet RNA score. To evaluate its clinical significance, this score was 3- times higher in PAD with (vs without) CLI (P=0.002). Further, after adjusting for age, sex, race, T2D, hypertension and coronary artery disease, the platelet score above (vs below) the median was associated with increased MACE (HR 2.8, 95% CI 1.4 to 5.6, P = 0.003). Conclusions: These findings demonstrate a unique platelet transcriptome in T2D that is associated with PAD severity and future risk of cardiovascular events. This work provides an important step toward the use of platelet RNA to unlock novel molecular mechanisms and inform future clinical outcomes.