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

• Published in: Circulation (New York, N.Y.) Vol. 108; no. 8; pp. 989 - 995
• Main Authors: FONTANA, Pierre, DUPONT, Annabelle, GANDRILLE, Sophie, BACHELOT-LOZA, Christilla, RENY, Jean-Luc, AIACH, Martine, GAUSSEM, Pascale
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 26.08.2003; American Heart Association, Inc
• Subjects: Adenosine Diphosphate - pharmacology; Adolescent; Adult; Alleles; Base Sequence; Biological and medical sciences; Blood and lymphatic vessels; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiology. Vascular system; Cyclic AMP - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Drug Resistance - genetics; Genetic Testing; Genetic Variation; Haplotypes; Heterozygote; Humans; Integrin beta3 - genetics; Male; Medical sciences; Membrane Proteins; Molecular Sequence Data; Platelet Aggregation - drug effects; Platelet Aggregation - genetics; Polymorphism, Genetic; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2Y12; Reference Values; Human; P2Y12 purinergic receptor; receptors; Cardiovascular disease; ADP; Genetic determinism; Thrombosis; platelets; Vascular disease; Aggregation; Platelet; genetics; Gene; Risk factor
• DOI: 10.1161/01.CIR.0000085073.69189.88
• ISSN: 0009-7322; 1524-4539

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. 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. 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.