A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.
Alleles
Blood Platelets
/ physiology
Cardiovascular Diseases
/ genetics
Embolism
/ genetics
Female
Genome-Wide Association Study
/ methods
Heart Failure
/ genetics
Humans
Lung
/ physiology
Male
Middle Aged
Neoplasms
/ genetics
Platelet Activation
/ genetics
Platelet Aggregation
/ genetics
Receptor, PAR-1
/ genetics
Receptors, Thrombin
/ genetics
Signal Transduction
/ genetics
Stroke
/ genetics
Thrombin
/ genetics
Cardiovascular Disease
GWAS
PAR-4
eQTL
platelets
regulatory
stroke
thrombin
thrombosis
venous thromboembolism
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
24
01
2020
accepted:
03
06
2020
pubmed:
11
7
2020
medline:
21
10
2020
entrez:
11
7
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 32649856
pii: S0002-9297(20)30196-8
doi: 10.1016/j.ajhg.2020.06.008
pmc: PMC7413854
pii:
doi:
Substances chimiques
Receptor, PAR-1
0
Receptors, Thrombin
0
Thrombin
EC 3.4.21.5
protease-activated receptor 4
JWE1M73YZN
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
211-221Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL066987
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK110805
Pays : United States
Informations de copyright
Published by Elsevier Inc.
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