Fontana Pierre, Dupont Annabelle, Gandrille Sophie, Bachelot-Loza Christilla, Reny Jean-Luc, Aiach Martine, Gaussem Pascale
Service d'Hématologie Biologique A, Hôpital Européen Georges Pompidou and Inserm Unité 428, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France.
Circulation. 2003 Aug 26;108(8):989-95. doi: 10.1161/01.CIR.0000085073.69189.88. Epub 2003 Aug 11.
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.
二磷酸腺苷（ADP）受体P2Y12在血小板聚集中起关键作用，心血管疾病患者中对其进行阻断所带来的益处证明了这一点。一些研究显示，体外ADP诱导的血小板聚集反应存在个体差异，但这种变异性的潜在机制尚不清楚。
我们检测了98名健康志愿者中ADP诱导的血小板聚集反应，并确定了对2 μmol/L ADP反应性高和低的两个表型组。这促使我们筛查最近发现的与Gi偶联的ADP受体基因P2Y12的序列变异。在由此确定的5个常见多态性中，4个处于完全连锁不平衡状态，确定了单倍型H1和H2，其等位基因频率分别为0.86和0.14。在整个研究人群中，H2等位基因的数量与对ADP的最大聚集反应相关（P = 0.007）。在10名选定的H2携带者中，ADP对血小板cAMP浓度的下调比对10名非携带者更明显。
在健康受试者中，ADP诱导的血小板聚集与P2Y12受体基因的单倍型相关。鉴于P2Y12受体在血小板功能中的关键作用，H2单倍型携带者可能有动脉粥样硬化血栓形成风险增加和/或对抑制血小板功能药物的临床反应较小的情况。
