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(Circulation. 2003;108:989.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Adenosine Diphosphate–Induced Platelet Aggregation Is Associated With P2Y₁₂ Gene Sequence Variations in Healthy Subjects

Pierre Fontana, MD; Annabelle Dupont, MSc; Sophie Gandrille, PhD; Christilla Bachelot-Loza, PhD; Jean-Luc Reny, MD, PhD; Martine Aiach, PhD; Pascale Gaussem, PhD

From the Service d’Hématologie Biologique A, Hôpital Européen Georges Pompidou and Inserm Unité 428, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France.

Correspondence to Pierre Fontana, Service d’Hématologie Biologique A, Hôpital Européen Georges Pompidou, 20 rue Leblanc, F-75908 Paris cedex 15, France. E-mail pierre.fontana{at}egp.ap-hop-paris.fr

Received July 9, 2002; de novo received April 2, 2003; revision received May 30, 2003; accepted June 3, 2003.

Background— The adenosine diphosphate (ADP) receptor P2Y₁₂ plays a pivotal role in platelet aggregation, as demonstrated by the benefit conferred by its blockade in patients with cardiovascular disease. Some studies have shown interindividual differences in ADP-induced platelet aggregation responses ex vivo, but the mechanisms underlying this variability are unknown.

Methods and Results— We examined ADP-induced platelet aggregation responses in 98 healthy volunteers, and we identified 2 phenotypic groups of subjects with high and low responsiveness to 2 µmol/L ADP. This prompted us to screen the recently identified G_i-coupled ADP receptor gene P2Y₁₂ for sequence variations. Among the 5 frequent polymorphisms thus identified, 4 were in total linkage disequilibrium, determining haplotypes H1 and H2, with respective allelic frequencies of 0.86 and 0.14. The number of H2 alleles was associated with the maximal aggregation response to ADP in the overall study population (P=0.007). Downregulation of the platelet cAMP concentration by ADP was more marked in 10 selected H2 carriers than in 10 noncarriers.

Conclusions— In healthy subjects, ADP-induced platelet aggregation is associated with a haplotype of the P2Y₁₂ receptor gene. Given the crucial role of the P2Y₁₂ receptor in platelet functions, carriers of the H2 haplotype may have an increased risk of atherothrombosis and/or a lesser clinical response to drugs inhibiting platelet function.

Key Words: platelets • genetics • receptors

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