Medicine and Health Sciences Commons^™

G Protein-Coupled Receptor Kinase 5 Regulates Thrombin Signaling In Platelets Via Par-1., Kate Downes, Xuefei Zhao, Nicholas S Gleadall, Harriet Mckinney, Carly Kempster, Joana Batista, Patrick L Thomas, Matthew Cooper, James V Michael, Roman Kreuzhuber, Katherine Wedderburn, Kathryn Waller, Bianca Varney, Hippolyte Verdier, Neline Kriek, Sofie E Ashford, Kathleen E Stirrups, Joanne L Dunster, Steven E Mckenzie, Willem H Ouwehand, Jonathan M Gibbins, Jing Yang, William J Astle, Peisong Ma

Cardeza Foundation for Hematologic Research

The interindividual variation in the functional response of platelets to activation by agonists is heritable. Genome-wide association studies (GWASs) of quantitative measures of platelet function have identified fewer than 20 distinctly associated variants, some with unknown mechanisms. Here, we report GWASs of pathway-specific functional responses to agonism by adenosine 5'-diphosphate, a glycoprotein VI-specific collagen mimetic, and thrombin receptor-agonist peptides, each specific to 1 of the G protein-coupled receptors PAR-1 and PAR-4, in subsets of 1562 individuals. We identified an association (P = 2.75 × 10-40) between a common intronic variant, rs10886430, in the G protein-coupled receptor kinase 5 gene (GRK5) …