Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury. Am J Hematol 2012 Feb;87(2):161-6
Date
01/10/2012Pubmed ID
22228373Pubmed Central ID
PMC4371854DOI
10.1002/ajh.22244Scopus ID
2-s2.0-84862954031 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 binding. We identified a novel association of SNP rs773857 with PMI (OR = 2.4, P = 0.004). rs773857 risk allele homozygotes have significantly increased platelet counts and platelets showed a significant increase in P-selectin release after activation (P = 0.004). We conclude that rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity.
Author List
Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Smith SA, Lichtner P, Collard CD, Shernan SK, Hartwig JH, Body SC, Hoffmeister KMAuthor
Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedBlood Platelets
Coronary Artery Bypass
Coronary Artery Disease
Dual Specificity Phosphatase 2
Female
Gene Expression
Heart Injuries
Homozygote
Humans
Middle Aged
Oligopeptides
P-Selectin
Perioperative Period
Platelet Activation
Platelet Count
Polymorphism, Single Nucleotide
Protein Binding
Receptors, Thrombin
Risk Factors
von Willebrand Factor