A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

ABSTRACT: Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10^-42) associated with increased thrombin-induced platelet aggregation (β = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associa

SUBMITTER: Rodriguez BAT 

PROVIDER: S-EPMC7413854 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature