title: Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race.
abstract: Human platelets express 2 thrombin receptors: protease-activated receptor (PAR)-1 and PAR4. Recently, we reported 3.7-fold increased PAR4-mediated aggregation kinetics in platelets from black subjects compared with white subjects. We now show that platelets from blacks (n = 70) express 14% more PAR4 protein than those from whites (n = 84), but this difference is not associated with platelet PAR4 function. Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Among these single nucleotide polymorphisms, rs773902 determines whether residue 120 in transmembrane domain 2 is an alanine (Ala) or threonine (Thr). Compared with the Ala120 variant, Thr120 was more common in black subjects than in white subjects (63% vs 19%), was associated with higher PAR4-induced human platelet aggregation and Ca2+ flux, and generated greater inositol 1,4,5-triphosphate in transfected cells. A second, less frequent F2RL3 variant, Phe296Val, was only observed in blacks and abolished the enhanced PAR4-induced platelet aggregation and 1,4,5-triphosphate generation associated with PAR4-Thr120. PAR4 genotype did not affect vorapaxar inhibition of platelet PAR1 function, but a strong pharmacogenetic effect was observed with the PAR4-specific antagonist YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole]. These findings may have an important pharmacogenetic effect on the development of new PAR antagonists.
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
authors.forename: Lukas M
authors.initials: LM
authors.lastname: Simon
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Cory R
authors.initials: CR
authors.lastname: Lindsay
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Xianguo
authors.initials: X
authors.lastname: Kong
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Raúl
authors.initials: R
authors.lastname: Teruel-Montoya
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Tourdot
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
authors.forename: Edward S
authors.initials: ES
authors.lastname: Chen
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA;
authors.forename: Shaun
authors.initials: S
authors.lastname: Coughlin
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH; and.
authors.forename: Marvin
authors.initials: M
authors.lastname: Nieman
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Statistics, Rice University, Houston, TX.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
mesh_terms: D044383:Black People / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics; D018179:Receptors, Thrombin / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D018179:Receptors, Thrombin; C112908:protease-activated receptor 4