A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways

Jones, Chris I.; Bray, Sarah; Garner, Stephen F.; Stephens, Jonathan; Bono, Bernard de; Angenent, W.; Bentley, David; Burns, Philippa; Coffey, Alison J.; Deloukas, Panos; Earthrowl, M. E.; Farndale, Richard W.; Hoylaerts, Marc; Koch, Kerstin; Rankin, Angela; Rice, Catherine M.; Rogers, Jane; Samani, Nilesh J.; Steward, M. W.; Walker, Adam; Watkins, Nicholas A.; Akkerman, Jan-Willem Ν.; Dudbridge, Frank; Goodall, Alison H.; Ouwehand, Willem H.

doi:10.1182/blood-2009-02-202614

Cited by 135 publications

(132 citation statements)

References 49 publications

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“…[1][2][3][4][5][6][7][8][9][10][11][12] At the same time, these and other studies of siblings, twins, and families with a history of coronary artery disease (CAD) have documented that intraindividual responsiveness is highly reproducible over time, regardless of the agonist tested or the chosen method of assessment. These findings strongly suggest that there is a high level of heritability of platelet function, and this has prompted numerous attempts to define the genetic basis for platelet function variability.…”

Section: Introductionmentioning

confidence: 92%

The genetics of normal platelet reactivity

Kunicki

Nugent

2010

Blood

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Genetic and environmental factors contribute to a substantial variation in platelet function seen among normal persons. Candidate gene association studies represent a valiant effort to define the genetic component in an era where genetic tools were limited, but the single nucleotide polymorphisms identified in those studies need to be validated by more objective, comprehensive approaches, such as genome-wide association studies (GWASs) of quantitative functional traits in much larger cohorts of more carefully selected normal subjects. During the past year, platelet count and mean platelet volume, which indirectly affect platelet function, were the subjects of GWAS. IntroductionInterindividual platelet responsiveness to a variety of agonists is highly variable, as documented in several studies of large cohorts of normal persons. [1][2][3][4][5][6][7][8][9][10][11][12] At the same time, these and other studies of siblings, twins, and families with a history of coronary artery disease (CAD) have documented that intraindividual responsiveness is highly reproducible over time, regardless of the agonist tested or the chosen method of assessment. These findings strongly suggest that there is a high level of heritability of platelet function, and this has prompted numerous attempts to define the genetic basis for platelet function variability. A summary of platelet functionTo fully appreciate the gene association studies, it is necessary to briefly summarize key aspects of platelet function and establish a molecular and physiologic basis for the selection of genes to study.When a blood vessel is damaged, circulating platelets interact with components of the extracellular matrix, particularly collagen, and a complex series of receptor-ligand interactions ensues that ultimately leads to the formation of a stable platelet plug or thrombus. This process is a continuum of at least 3 phases that we can describe as initiation, extension, and consolidation, each of which entails the cooperation of a different group of receptors.In the initiation phase, plasma von Willebrand factor (VWF) binds to collagen via its A3 domain and becomes structurally altered such that its A1 domain then binds to the platelet membrane receptor glycoprotein Ib-IX-V complex (GPIb complex). It is the GPIb␣ or larger subunit of GPIb that makes direct contact with VWF. This association is a requisite step in the adhesion of platelets to exposed thrombogenic surfaces at sites of vessel wall injury or in regions of atherosclerotic plaque rupture. Concurrently, a more stable platelet monolayer is formed on the collagen surface mediated predominantly by the platelet-specific receptor glycoprotein VI (GPVI) and platelet integrin ␣ 2 ␤ 1 .The engagement of these receptors enhances platelet activation leading to the extension phase, mediated largely by the conversion of prothrombin to thrombin at the activated platelet surface and the secretion of active compounds from platelet granules (␣-granules and ␦-granules), which can further stimulate platelets. One of...

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Section: Introductionmentioning

confidence: 92%

The genetics of normal platelet reactivity

Kunicki

Nugent

2010

Blood

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“…Recently, Jones et al (26), used a functional genomics approach to compare a relatively large number of SNPs (n = 1,327) in a selected group of candidate genes (n = 97), resulting in the identification of 17 independently associated SNPs that account for 48% of the variation in platelet reactivity induced by ADP. Even more recently, Johnson et al (27) performed a genome-wide meta-analysis of 2.5 million SNPs in 4,831 subjects to identify three loci associated with ADP-induced platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

Frelinger¹,

Michelson²,

Wiviott³

et al. 2011

Thromb Haemost

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SummaryIt was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y 12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade with high-dose clopidogrel or even higher level P2Y 12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

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“…For example, 17 novel singlenucleotide polymorphisms appear to account for just half of the large variability in platelet function measured even off-treatment, 10 which strongly correlates with on-treatment platelet function. 11 Similarly, a number of clinical factors (increasing age, acute coronary syndrome, decreased left ventricular function, diabetes mellitus, and renal insufficiency) are also independently associated with on-treatment platelet function.…”

Section: Article See P 512mentioning

confidence: 99%

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

Steinhubl¹

2010

Circulation

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A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways

Cited by 135 publications

References 49 publications

The genetics of normal platelet reactivity

The genetics of normal platelet reactivity

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

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