Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury.
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.
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. jmuehlschlegel@partners.org
Jochen D
JD
Muehlschlegel
Tjörvi E
TE
Perry
Kuang-Yu
KY
Liu
Amanda A
AA
Fox
Shane A
SA
Smith
Peter
P
Lichtner
Charles D
CD
Collard
Stanton K
SK
Shernan
John H
JH
Hartwig
Simon C
SC
Body
Karin M
KM
Hoffmeister
D000368:Aged; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001026:Coronary Artery Bypass / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000097:blood / Q000473:pathology / Q000601:surgery*; D054641:Dual Specificity Phosphatase 2 / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006335:Heart Injuries / Q000097:blood* / Q000209:etiology / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism; D059035:Perioperative Period; D015539:Platelet Activation / Q000187:drug effects; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D018179:Receptors, Thrombin / Q000235:genetics*; D012307:Risk Factors; D014841:von Willebrand Factor / Q000378:metabolism
D009842:Oligopeptides; D019007:P-Selectin; D018179:Receptors, Thrombin; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; D014841:von Willebrand Factor; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; C112908:protease-activated receptor 4