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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:252.)
© 2005 American Heart Association, Inc.

Thrombosis

Dimorphism in the P2Y1 ADP Receptor Gene Is Associated With Increased Platelet Activation Response to ADP

Simon L. Hetherington; Ravi K. Singh; David Lodwick; John R. Thompson; Alison H. Goodall; Nilesh J. Samani

From the Department of Cardiovascular Sciences, University of Leicester, United Kingdom.

Correspondence to Professor N.J. Samani, Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, LE3 9QP, UK. E-mail njs{at}le.ac.uk

Objective— The platelet ADP receptors P2Y1 and P2Y12 play a pivotal role in platelet aggregation. There is marked interindividual variation in platelet response to ADP. We studied whether genetic variants in the P2Y1 or P2Y12 genes affect platelet response to ADP.

Methods and Results— The P2Y1 and P2Y12 genes were screened for polymorphisms. Associations between selected polymorphisms and the platelet response to ADP (0.1, 1.0, and 10 µmol/L), assessed by whole blood flow cytometric measurement of fibrinogen binding to activated glycoprotein IIb-IIIa, were then determined in 200 subjects. Five polymorphisms were found in the P2Y1 gene and 11 in the P2Y12 gene. All polymorphisms were silent. A P2Y1 gene dimorphism, 1622AG, was associated with a significant (P=0.007) effect on platelet ADP response, with a greater response in carriers of the G allele (frequency 0.15). The effect was seen at all concentrations of ADP but greatest at 0.1 µmol/L ADP, where the response in GG homozygotes was on average 130% higher than that seen in AA homozygotes (P=0.006).

Conclusions— A common genetic variant at the P2Y1 locus is associated with platelet reactivity to ADP. This genotype effect partly explains the interindividual variation in platelet response to ADP and may have clinical implications with regard to thrombotic risk.

ADP is an important mediator of platelet aggregation. In this study, we show that a polymorphism (1622AG) in the P2Y1 ADP receptor gene is associated with a significant effect on platelet ADP response. This genotype effect explains some of the interindividual variability in platelet reactivity and may influence thrombotic risk.

Key Words: platelets • thrombosis • genes • receptors • adenosine diphosphate

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