Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects.
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.


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 micromol/L ADP. This prompted us to screen the recently identified Gi-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.
Fontana
Pierre
P
Service d'Hématologie Biologique A, Hôpital Européen Georges Pompidou and Inserm Unité 428, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France. pierre.fontana@egp.ap-hop-paris.fr
Dupont
Annabelle
A
Gandrille
Sophie
S
Bachelot-Loza
Christilla
C
Reny
Jean-Luc
JL
Aiach
Martine
M
Gaussem
Pascale
P
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics*; D011110:Polymorphism, Genetic; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12; D012016:Reference Values
D039661:Integrin beta3; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000242:Cyclic AMP