title: Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS).
abstract: Platelet reactivity, an important factor in hemostasis and chronic disease, has widespread inter-individual variability with a substantial genetic contribution. Previously, our group performed a genome-wide association study of platelet reactivity identifying single nucleotide polymorphisms (SNPs) associated with ADP- and epinephrine- induced aggregation, including SNPs in MRVI1, PIK3CG, JMJD1C, and PEAR1, among others. Here, we assessed the association of these previously identified SNPs with ADP-, thrombin-, and shear- induced platelet aggregation. Additionally, we sought to expand the association of these SNPs with blood cell counts and hemostatic factors. To accomplish this, we examined the association of 12 SNPs with seven platelet reactivity and various hematological measures in 1300 middle-aged men in the Caerphilly Prospective Study. Nine of the examined SNPs showed at least suggestive association with platelet reactivity. The strongest associations were with rs12566888 in PEAR1 to ADP-induced (p = 1.51 × 10(-7)) and thrombin-induced (p = 1.91 × 10(-6)) reactivity in platelet rich plasma. Our results indicate PEAR1 functions in a relatively agonist independent manner, possibly through subsequent intracellular propagation of platelet activation. rs10761741 in JMJD1C showed suggestive association with ADP-induced reactivity (p = 1.35 × 10(-3)), but its strongest associations were with platelet-related cell counts (p = 1.30 × 10(-9)). These associations indicate variation in JMJD1C influences pathways that modulate platelet development as well as those that affect reactivity. Associations with other blood cell counts and hemostatic factors were generally weaker among the tested SNPs, indicating a specificity of these SNPs' function to platelets. Future genome-wide analyses will further assess association of these genes and identify new genes important to platelet biology.
authors.affiliation: The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA, 01702, USA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA, 01702, USA.|Biostatistics Program, Boston University, Boston, MA, USA.
authors.forename: Luting
authors.initials: L
authors.lastname: Xue
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Beswick
authors.affiliation: The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA, 01702, USA. johnsonad2@nhlbi.nih.gov.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA. johnsonad2@nhlbi.nih.gov.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: C485784:IRAG1 protein, human; D008565:Membrane Proteins; C502809:PEAR1 protein, human; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D000244:Adenosine Diphosphate; C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D004837:Epinephrine
keywords: Blood platelets; Platelet aggregation; Platelet count; SNPs; Thrombin