Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1
(COX1) that have been incompletely characterized. Transcriptomics can
comprehensively characterize the on- and off-target effects of
medications. We used a systems pharmacogenomics approach of aspirin
exposure in volunteers coupled with serial platelet function and
purified platelet mRNA sequencing to test the hypothesis that aspirin’s
effects on the platelet transcriptome are associated with platelet
function. We prospectively recruited 74 adult volunteers for a
randomized cross over study of 81- vs. 325 mg/day, each for 4 weeks.
Using mRNA sequencing of purified platelets collected before and after
each 4-week exposure, we identified 208 aspirin-responsive genes with no
evidence for dosage effects. In independent cohorts of healthy
volunteers and patients with diabetes we validated aspirin’s effects on
five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2, and HLA-DRA.
Functional characterization of the effects of aspirin on mRNA as well as
platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor
of protein synthesis. Database searches for small molecules that
mimicked the effects of aspirin on platelet gene expression in
vitro identified aspirin but no other molecules that share aspirin’s
known mechanisms of action. The effects of aspirin on platelet mRNA were
correlated with higher levels of platelet function both at baseline and
after aspirin exposure – an effect that counteracts aspirin’s known
antiplatelet effect. In summary, this work collectively demonstrates a
dose-independent effect of aspirin on the platelet transcriptome that
counteracts the well-known antiplatelet effects of aspirin.