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Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS)

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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.

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Abbreviations

SNP:

Single nucleotide polymorphism

GWAS:

Genome-wide association study

PRP:

Platelet rich plasma

CaPs:

Caerphilly Prospective Study in men

PLT:

Platelet count

MPV:

Mean platelet volume

LTA:

Light transmission aggregometry

WBC:

White blood cell

RBC:

Red blood cell

MCV:

Mean corpuscular volume

MCH:

Mean corpuscular hemoglobin

MAF:

Minor allele frequency

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Acknowledgments

The authors wish to acknowledge the subjects who volunteered their time and effort as well as the National Heart, Lung and Blood Institute Intramural Research Program funding to Dr. Chris J. O’Donnell for the support of SNP genotyping. The Caerphilly Prospective Study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The Caerphilly DNA Bank was established by an MRC Grant (G9824960).

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Authors and Affiliations

  1. The Framingham Heart Study, 73 Mt. Wayte Ave. Suite #2, Framingham, MA, 01702, USA

    John D. Eicher, Luting Xue & Andrew D. Johnson

  2. Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA

    John D. Eicher & Andrew D. Johnson

  3. Biostatistics Program, Boston University, Boston, MA, USA

    Luting Xue

  4. School of Social and Community Medicine, University of Bristol, Bristol, UK

    Yoav Ben-Shlomo

  5. School of Clinical Sciences, University of Bristol, Bristol, UK

    Andrew D. Beswick

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  1. John D. Eicher
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  2. Luting Xue
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Correspondence to Andrew D. Johnson.

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Eicher, J.D., Xue, L., Ben-Shlomo, Y. et al. Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS). J Thromb Thrombolysis 41, 343–350 (2016). https://doi.org/10.1007/s11239-015-1290-7

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  • DOI: https://doi.org/10.1007/s11239-015-1290-7

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