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

dc.rights.licenseopenen_US
dc.contributor.authorRODRIGUEZ, B. A. T.
dc.contributor.authorBHAN, A.
dc.contributor.authorBESWICK, A.
dc.contributor.authorELWOOD, P. C.
dc.contributor.authorNIIRANEN, T. J.
dc.contributor.authorSALOMAA, V.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorMORANGE, P. E.
dc.contributor.authorCIVELEK, M.
dc.contributor.authorBEN-SHLOMO, Y.
dc.contributor.authorSCHLAEGER, T.
dc.contributor.authorCHEN, M. H.
dc.contributor.authorJOHNSON, A. D.
dc.date.accessioned2021-02-15T13:54:11Z
dc.date.available2021-02-15T13:54:11Z
dc.date.issued2020
dc.identifier.issn1537-6605 (Electronic) 0002-9297 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/26246
dc.description.abstractEnDual 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 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.
dc.language.isoENen_US
dc.subjectVINTAGE
dc.title.enA Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling
dc.title.alternativeAm J Hum Geneten_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.ajhg.2020.06.008en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed32649856en_US
bordeaux.journalAmerican Journal of Human Geneticsen_US
bordeaux.page211-221en_US
bordeaux.volume107en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue2en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03141739
hal.version1
hal.date.transferred2021-02-15T13:54:15Z
hal.exporttrue
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