Article

Genetics of platelet reactivity in normal, healthy individuals.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Journal of Thrombosis and Haemostasis (impact factor: 5.73). 10/2009; 7(12):2116-22. DOI:10.1111/j.1538-7836.2009.03610.x pp.2116-22
Source: PubMed

ABSTRACT The Platelet Function Analyzer-100 (PFA-100) is widely used to measure platelet reactivity in whole blood under high shear.
To characterize the genetic component of platelet reactivity among normal individuals, using the PFA-100.
We compared baseline platelet reactivity with sex, age, platelet count, hematocrit, plasma von Willebrand factor antigen (VWF:Ag), and alleles of seven candidate genes: integrin subunits alpha2 (ITGA2) and beta3 (ITGB3), platelet glycoproteins GPIbalpha (GP1BA) and GPVI (GP6), purinogenic receptors (P2RY1 and P2RY12) and cyclooxygenase-1 (COX1).
Based on linear and logistic regression models, we report an inverse correlation between baseline closure time (CT) initiated by collagen plus epinephrine (CEPI) and plasma VWF:Ag level, ITGA2 807T and P2RY1 893C, and an inverse correlation between baseline CT initiated by collagen plus adenosine diphosphate (CADP) and P2RY1 893C or GP1BA -5C.
These results indicate that genetic polymorphisms in ITGA2 and P2RY1 combine with plasma VWF:Ag levels to modulate baseline platelet reactivity in response to collagen plus EPI, while genetic differences in P2RY1 and GP1BA significantly effect platelet responses to collagen plus ADP. Our results demonstrate that the PFA-100 can be used to evaluate the effects of genetic predictors of platelet function.

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    Article: Enhanced binding of poly(ADP-ribose)polymerase-1 and Ku80/70 to the ITGA2 promoter via an extended cytosine-adenosine repeat.
    Yann Cheli, Shirley A Williams, Robert Ballotti, Diane J Nugent, Thomas J Kunicki
    [show abstract] [hide abstract]
    ABSTRACT: We have identified a cytosine-adenosine (CA) repeat length polymorphism in the 5'-regulatory region of the human integrin alpha2 gene ITGA2 that begins at -605. Our objective was to establish the contribution of this polymorphism to the regulation of integrin alpha2beta1 expression, which is known to vary several-fold among normal individuals, and to investigate the underlying mechanism(s). In combination with the SNP C-52T, previously identified by us as a binding site for the transcription factor Sp1, four ITGA2 haplotypes can be distinguished, in the order in which they enhance ITGA2 transcription: (CA)(12)/-52C>(CA)(11)/-52C>(CA)(11)/-52T>(CA)(10)/-52T. By DNA affinity chromatography and chromatin immunoprecipitation (ChIP) assays, we show that poly (ADP-ribose)polymerase-1 (PARP-1) and Ku80/70 bind specifically and with enhanced affinity to the longer (CA)(12) repeat alleles. The increased binding of PARP-1 and Ku80/70, known components of transcription co-activator complexes, to the longer (CA)(12) alleles of ITGA2 coincides with enhanced alpha2beta1 expression. The most likely explanation for these findings is that PARP-1 and Ku80/70 contribute to the transcriptional regulation of ITGA2. These observations provide new insight into the mechanisms(s) underlying haplotype-dependent variability in integrin alpha2beta1 expression in human platelets and other cells.
    PLoS ONE 01/2010; 5(1):e8743. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

adenosine diphosphate
 
alleles
 
baseline closure time
 
baseline CT
 
baseline platelet reactivity
 
candidate genes
 
genetic component
 
GP1BA -5C
 
integrin subunits alpha2
 
inverse correlation
 
measure platelet reactivity
 
modulate baseline platelet reactivity
 
plasma von Willebrand factor antigen
 
platelet count
 
platelet function
 
Platelet Function Analyzer-100
 
platelet glycoproteins GPIbalpha
 
platelet reactivity
 
purinogenic receptors
 
whole blood