A1 Refereed original research article in a scientific journal
A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling
Authors: Rodriguez Benjamin AT, Bhan Arunoday, Beswick Andrew, Elwood Peter C, Niiranen Teemu J, Salomaa Veikko, Tregouet David-Alexandre, Morange Pierre-Emmanuel, Civelek Mete, Ben-Shlomo Yoav, Schlaeger Thorsten, Chen Ming-Huei, Johnson Andrew D; FinnGen Study
Publisher: CELL PRESS
Publication year: 2020
Journal: American Journal of Human Genetics
Journal name in source: AMERICAN JOURNAL OF HUMAN GENETICS
Journal acronym: AM J HUM GENET
Volume: 107
Issue: 2
First page : 211
Last page: 221
Number of pages: 11
ISSN: 0002-9297
eISSN: 1537-6605
DOI: https://doi.org/10.1016/j.ajhg.2020.06.008
Web address : https://www.sciencedirect.com/science/article/pii/S0002929720301968?via%3Dihub
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 x 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 associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.
