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Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

Leonard C Edelstein1, Lukas M Simon2, Cory R Lindsay1

  • 1Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Philadelphia, PA;

Blood
|October 9, 2014
PubMed

Insights

Genetic variations in the protease-activated receptor 4 (PAR4) gene influence human platelet aggregation. Specific PAR4 variants, like Thr120, are more common in Black individuals and enhance platelet response, impacting drug development.

Area of Science:

  • * Genetics and Molecular Biology
  • * Hematology and Thrombosis
  • * Pharmacogenomics

Background:

  • * Human platelets possess two thrombin receptors: protease-activated receptor (PAR)-1 and PAR4.
  • * Previous research indicated significantly higher PAR4-mediated platelet aggregation in Black individuals compared to White individuals.
  • * Platelet PAR4 protein expression differences were noted between racial groups but not linked to functional variations.

Purpose of the Study:

  • * To investigate the genetic underpinnings of differential PAR4-mediated platelet aggregation.
  • * To identify specific single nucleotide polymorphisms (SNPs) in the PAR4 gene (F2RL3) associated with platelet aggregation.
  • * To explore the functional and pharmacogenetic implications of identified PAR4 variants.

Main Methods:

  • * Quantitative trait locus analysis was employed to identify SNPs in the F2RL3 gene linked to PAR4-induced platelet aggregation.
  • * Genotyping was performed for specific SNPs, including rs773902, which determines the amino acid at residue 120 (Alanine or Threonine).
  • * Platelet aggregation, calcium (Ca2+) flux, and inositol 1,4,5-triphosphate generation were measured in response to PAR4 activation, with and without specific antagonists.

Main Results:

  • * Three common F2RL3 SNPs were associated with PAR4-induced platelet aggregation.
  • * The PAR4-Thr120 variant (rs773902) was more prevalent in Black subjects and correlated with increased platelet aggregation, Ca2+ flux, and inositol 1,4,5-triphosphate generation.
  • * A second variant, F2RL3 Phe296Val, found only in Black individuals, abrogated the enhanced aggregation and signaling associated with PAR4-Thr120. Pharmacogenetic effects were observed with the PAR4 antagonist YD-3.

Conclusions:

  • * Specific genetic variants within the PAR4 gene (F2RL3) significantly influence human platelet aggregation.
  • * The PAR4-Thr120 variant contributes to heightened platelet reactivity in certain populations and impacts responses to PAR4-specific antagonists.
  • * These findings highlight the importance of pharmacogenetics in the development of novel PAR antagonists.

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