Role of the P2Y12 gene polymorphism in platelet responsiveness to clopidogrel in healthy subjects

Abstract

To cite this article: Bura A, Bachelot-Loza C, Dali Ali F, Aiach M, Gaussem P. Role of the P2Y 12 gene polymorphism in platelet responsiveness to clopidogrel in healthy subjects. J Thromb Haemost 2006;4: 2096-7. Clopidogrel is an inhibitor of platelet function. Its active metabolite irreversibly blocks the platelet ADP receptor P2Y 12 [1] and prevents ischemic events in patients with atherosclerosis [2]. The antiplatelet effect of clopidogrel shows wide interindividual variability and in 5-30% of patients the recommended dose of 75 mg day )1 fails to inhibit platelet aggregation ex vivo [3][4][5]. We examined the role of the gain-of-function polymorphism (H2 allele) of the P2Y 12 gene [6], which encodes the clopidogrel target receptor, in the extent of clopidogrel pharmacodynamic response.To investigate the possible influence of the H2 allele free from confounding factors, such as medications or cardiovascular diseases, we evaluated clopidogrel responsiveness in young healthy subjects during a 1-week oral course of clopidogrel 75 mg day . Among 225 Caucasian men aged 18-35 years screened for the H1H2 genotype [7], we consecutively included 29 healthy volunteers (14 H1H1, 11 H1H2, and 4 H2H2). The study was approved by the Paris-Cochin ethics committee and all the subjects gave their written informed consent. The volunteers were asked to come to the Clinical Investigations Center each day at 09:00 hours where they were given a standard dose of clopidogrel 75 mg once daily for 7 days in the presence of medical staff. Blood samples for pharmacodynamic studies were drawn just before the first clopidogrel intake on days 1, 2, 3, 4, 5, and 7, and on days 9, 10, 11, and 14. Platelet response to 10 lmol L )1 ADP was evaluated with platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation, which is specific for P2Y 12 inhibition. Aggregation studies were performed at baseline, on treatment, and after treatment completion at 37°C using a photometric method on a four-channel aggregometer (Regulest, Amneville, France). ADP-induced aggregation (10 lmol L )1 final concentration, Sigma-Aldrich, St-Quentin Fallavier, France) was reported as maximal aggregation or as a percentage of baseline aggregation. VASP was measured in whole blood at baseline, on day 4 and on day 7 of clopidogrel intake using a flow cytometric assay (Platelet VASPÒ, Diagnostica Stago, Biocytex, Marseille, France) adapted to a Cy-Flow apparatus (Partec GmbH, SteGenevie`ve-des-Bois, France 78.0) in H1H2 subjects; and 79.0% (IQR 76.5; 81.0) in H2H2 subjects (P ¼ 0.25). The aggregation fell significantly between days 1 and 7 of clopidogrel intake in the whole population [median at day 7 (IQR): 54% (45.5; 65.5), P < 0.0001], but the response did not differ between H1H1 subjects and H1H2 + H2H2 subjects (P ¼ 0.58). However, while median platelet aggregation significantly fell in H1H1 [54% (46; 68)] and H1H2 [49% (29; 59)] groups on day 7 of clopidogrel intake, no significant fall occurred in the H2H2 subjects [76% (65; 82), P < 0...

Coexisting Polymorphisms of P2Y12 and CYP2C19 Genes as a Risk Factor for Persistent Platelet Activation With Clopidogrel

“…15 Only the study by Bura et al confirmed an association between higher platelet optical aggregation and carriers of 2 H2 haplotypes, which suggests a potential but rather weak effect. 16 In the present study, carriers of the C allele of P2Y12 (after exclusion of CYP2C19 polymorphism carriers) did not have a significantly decreased platelet response to ADP.…”

Frequency of single nucleotide platelet receptor gene polymorphism (P2Y12-i744T>C) in coronary artery disease patients among Tamilian population

“…Further, studies in other ethnics also showed potential conflicting associations. Few studies done on different population concluded that the carriers with H2 alleles have higher propensity for CAD with maximal platelet aggregation in response to ADP (Fontana et al 2003a) (Bura et al 2006) (Cavallari et al 2007). However, on the contrary, similar studies concluded that the gene sequence variation in P2Y12 did not contribute to the risk of development of CAD in Caucasian (Smith et al 2006) (Lev et al 2007) (Zee et al 2008) (Malek et al 2008), in French (Cuisset et al 2007), in Brazilian (Schettert et al 2006), in Mexican (Isordia-Salas et al 2012, in Italian (Giusti et al 2007), and Korean population (Lee et al 2011) (Jang et al 2012).…”

P2 receptors and platelet function

“…Two haplotypes have been identified, designated as H1 and H2, the latter being proposed to be linked to enhanced platelet reactivity to ADP [97] and to a diminished response to clopidogrel [98] and associated with increased risks for peripheral arterial disease [99] and coronary artery disease [100]. However, these results were not confirmed in latter studies [101][102][103]. It thus appears that polymorphisms of the non-coding region of the P2Y 12 receptor gene do not have any impact on the receptor function nor on the individual responsiveness to clopidogrel.…”