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

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

  • Am J Hum Genet. 2020 Aug 6;107(2):211-221. doi: 10.1016/j.ajhg.2020.06.008.
Benjamin A T Rodriguez 1,  Arunoday Bhan 2,  Andrew Beswick 3,  Peter C Elwood 4,  Teemu J Niiranen 5,  Veikko Salomaa 6,  FinnGen Study,   David-Alexandre Trégouët 7,  Pierre-Emmanuel Morange 8,  Mete Civelek 9,  Yoav Ben-Shlomo 10,  Thorsten Schlaeger 2,  Ming-Huei Chen 1,  Andrew D Johnson 11
Affiliations

Affiliations

  • 1 National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA 01702, USA.
  • 2 Boston Children's Hospital, Boston, MA 02644, USA.
  • 3 School of Clinical Sciences, University of Bristol, Bristol, BS8 1TH UK.
  • 4 Division of Population Medicine, Cardiff University, Cardiff, CF14 4YS UK.
  • 5 Finnish Institute for Health and Welfare, Helsinki, FI-00271 Finland; Department of Medicine, Turku University Hospital and University of Turku, Turku, 20521 Finland.
  • 6 Finnish Institute for Health and Welfare, Helsinki, FI-00271 Finland.
  • 7 INSERM UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, 333076 Bordeaux, France.
  • 8 Laboratory of Haematology, La Timone Hospital, 13885 Marseille, France; Centre for Cardiovascular and Nutrition Research, Aix-Marseille Université, INSERM, INRA, 13885 Marseille, France; Centre de Ressources Biologiques Assistance Publique-Hôpitaux de Marseille, HemoVasc, 13885 Marseille, France.
  • 9 Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
  • 10 School of Social and Community Medicine, University of Bristol, Bristol, BS8 1TH UK.
  • 11 National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA 01702, USA. Electronic address: johnsonad2@nhlbi.nih.gov.
PMID: 32649856 DOI: 10.1016/j.ajhg.2020.06.008
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 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.

Keywords

Cardiovascular Disease; GWAS; PAR-4; eQTL; platelets; regulatory; stroke; thrombin; thrombosis; venous thromboembolism.

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