Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction

Abstract

Transcripts in platelets are largely produced in precursor megakaryocytes but remain physiologically-active as platelets translate RNAs and regulate protein/RNA levels. Recent studies using transcriptome sequencing (RNA-seq) characterized the platelet transcriptome in limited numbers of non-diseased individuals. Here, we expand upon these RNA-seq studies by completing RNA-seq in platelets from 32 patients with acute myocardial infarction (MI). Our goals were to characterize the platelet transcriptome using a population of patients with acute MI and relate gene expression to platelet aggregation measures and ST-segment elevation MI (STEMI) (n=16) versus non-STEMI (NSTEMI) (n=16) subtypes. Similar to other studies, we detected 9,565 expressed transcripts, including several known platelet-enriched markers (e.g., PPBP, OST4). Our RNA-seq data strongly correlated with independently ascertained platelet expression data and showed enrichment for platelet-related pathways (e.g., wound response, hemostasis, and platelet activation), as well as actin-related and post-transcriptional processes. Several transcripts displayed suggestively higher (FBXL4, ECHDC3, KCNE1, TAOK2, AURKB, ERG, and FKBP5) and lower (MIAT, PVRL3and PZP) expression in STEMI platelets compared to NSTEMI. We also identified transcripts correlated with platelet aggregation to TRAP (ATP6V1G2, SLC2A3), collagen (CEACAM1, ITGA2), and ADP (PDGFB, PDGFC, ST3GAL6). Our study adds to current platelet gene expression resources by providing transcriptome-wide analyses in platelets isolated from patients with acute MI. In concert with prior studies, we identify various genes for further study in regards to platelet function and acute MI. Future platelet RNA-seq studies examining more diverse sets of healthy and diseased samples will add to our understanding of platelet thrombotic and non-thrombotic functions.

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

“…Asterisk (*) indicates variants (11/18) that showed evidence of replication (p < 0.05, same direction of effect). If multiple genes/transcripts were annotated to a variant, the transcript more expressed in Eicher et al 32 (Table S22) (p < 0.001) (Tables 5, S18, and S19). The most strongly associated SNVs were located in genes implicated with platelet reactivity in prior GWASs, including PEAR1, MRVI1 (MIM: 604673), JMJD1C, and PIK3CG (MIM: 601232).…”

“…Using platelet RNA-seq data from 32 subjects with MI, we found that almost all of the genes closest to our previously unreported associated SNVs or marginal SNVs with evidence of replication were expressed in platelets, indicating the feasibility of potential functional roles in the relevant target cell type (Table S22). 32 …”

“…Asterisks (*) indicate variants (20/32) showing evidence of replication (p < 0.05, same direction of effect). If multiple genes/transcripts were annotated to a variant, the transcript most expressed in Eicher et al 32 (Table S22) We show variants in previously unreported MPV loci (n ¼ 18) and retained after conditional analyses in European ancestry (EA) (p < 2.59 3 10 À7 ) and all ancestry (All) (p < 2.20 3 10 À7 ) analyses. Associations in African ancestry (AA) had previously been reported in the literature (Table S11).…”

Slowed decay of mRNAs enhances platelet specific translation

“…It should serve as a valuable resource to understand normal platelet function and its disruption in disease. [89][90][91][92][93][94][95] …”

Personalized medicine in thrombosis: back to the future

“…[79][80][81] Transcriptomewide association studies also provide an unbiased approach to novel functional gene discovery; eg, miRNAs associated with myocardial infarction. 82 Relevant to hemostasis/thrombosis, RNA is most easily available from platelets, which reflects the megakaryocyte transcriptome.…”