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

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.