Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The platelet P2Y₁₂receptor plays a key role in platelet activation. The H2 haplotype of the P2Y₁₂receptor gene (<it>P2RY12</it>) has been found to be associated with maximal aggregation response to adenosine diphosphate (ADP) and with increased risk for peripheral arterial disease. No data are available on its association with coronary artery disease (CAD).</p> <p>Methods </p> <p>The H2 haplotype of the <it>P2RY12 </it>was determined in 1378 unrelated patients of both sexes selected according to the presence of significant coronary artery disease (CAD group) or having normal coronary angiogram at cardiac catheterization (CAD-free group). Significant coronary artery disease was angiographically determined, and was defined as a greater than 50% visually estimated luminal diameter stenosis in at least one major epicardial coronary artery.</p> <p>Results</p> <p>In the studied population 71.9% had CAD (n = 991) and 28.1% had normal coronary angiogram (n = 387). H2 haplotype carriers were more frequent in the CAD group (p = 0.03, OR = 1.36, 95%CI = 1.02–1.82). The H2 haplotype was significantly associated with CAD in non-smokers (p = 0.007, OR = 1.83 95%CI = 1.17–2.87), but not in smokers. The association remained significant after adjustment for other covariates (age, triglycerides, HDL, hypertension, diabetes) by multivariate logistic regression (p = 0.004, OR = 2.32 95%CI = 1.30–4.15).</p> <p>Conclusion</p> <p>Gene sequence variations of the P2Y₁₂receptor gene are associated with the presence of significant CAD, particularly in non-smoking individuals.</p

A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days.

AIMS: We sought to test whether an increase in the clopidogrel maintenance dose results in increased inhibition of platelet aggregation. METHODS AND RESULTS: Sixty patients after pre-treatment with 600 mg of clopidogrel and within 12 h after successful PCI were included in this trial. They were allocated to receive one of two clopidogrel daily maintenance doses (75 or 150 mg) for 30 days in a double-blind randomized manner. Platelet function was evaluated 30 days after the intervention with optical aggregometry and with a new point-of-care test (VerifyNowtrade mark P2Y12 assay). Maximal 5 microM ADP-induced platelet aggregation 30 days after PCI in the group treated with 150 mg/day clopidogrel (45.1 +/- 20.9%) was significantly lower than in the group treated with 75 mg/day (65.3 +/- 12.1%; P < 0.001). The VerifyNowtrade mark P2Y12 assay also indicated a higher degree of platelet function inhibition in the group treated with 150 mg/day (60.0 +/- 72.0 P2Y12 Reaction Units) than in the group treated with 75 mg/day (117.0 +/- 64.3 P2Y12 Reaction Units; P = 0.004). CONCLUSION: Administration of a 150 mg oral maintenance dose of clopidogrel results in more intense inhibition of platelet aggregation than administration of the currently recommended 75 mg maintenance dose

Assessment of platelet response to clopidogrel with multiple electrode aggregometry, the VerifyNow P2Y12 analyzer and platelet Vasodilator-Stimulated Phosphoprotein flow cytometry.

Multiple electrode platelet aggregometry (MEA) adenosine diphosphate (ADP) test is able to detect the platelet response to clopidogrel. The values obtained with MEA ADPtest correlate with those obtained with light transmission aggregometry and peri-interventional MEA ADPtest measurements are highly associated with the risk of early stent thrombosis after percutaneous coronary intervention. The main purpose of the present study was to correlate MEA ADPtest with the VerifyNow P2Y12 analyzer, Platelet VASP flow cytometry and the MEA ADPtest HS in order to test if these assays can substitute for each other. Blood samples from 60 consecutive patients scheduled for coronary angiography before and after administration of 600 mg of clopidogrel were analyzed. The correlation of MEA ADPtest with the other whole blood tests was moderate. The following order for the degree of correlation with MEA ADPtest for postclopidogrel values was found: MEA ADPtest HS (R = 0.83) > VerifyNow P2Y12 (R = 0.47) > Platelet VASP (R = 0.35). Of the 12 patients in the upper quintile of postclopidogrel values according to MEA ADPtest, seven were in the upper quintile according to VerifyNow P2Y12 (P < 0.001), six were in the upper quintile according to MEA ADPtest HS (P = 0.004) and three were in the upper quintile according to VASP (P = 0.63). Therefore, the studied whole blood assays cannot substitute for each other. Each assay with prognostic significance will have to undergo the ultimate test for individualized antiplatelet therapy in form of an adequately powered randomized clinical trial that shows that adjustment of antiplatelet therapy is beneficial for the patient

P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose.

A large variability in the antiplatelet response to clopidogrel has been consistently reported. Recently, a P2Y12 haplotype was shown to be associated with enhanced adenosine diphosphate (ADP)-induced platelet aggregation in healthy volunteers. The aim of this study was to test in patients (n = 416) scheduled for coronary artery stenting whether P2Y12 haplotype H2 carriage is associated with increased ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Blood was drawn from the arterial sheath at least 2 h after administration of 100 mg aspirin and 600 mg clopidogrel. ADP-induced platelet aggregation was assessed in platelet-rich plasma with light-transmission aggregometry. P2Y12 haplotypes (H1/H2) and P2Y12 C32T genotypes were determined with TaqMan assays. Haplotype combinations and genotypes were not associated with parameters of ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Maximal ADP (5 mumol/l)-induced platelet aggregation was similar in patients carrying haplotype H2 and homozygous carriers of haplotype H1 (43.9 +/- 21.4 versus 43.2 +/- 21.1%, respectively; P = 0.77). Carriage of P2Y12 H2 haplotype does not seem to affect the platelet response to a 600 mg loading dose of clopidogrel in coronary artery disease patients prior to stenting

G protein beta 3 subunit 825T allele carriage and risk of coronary artery disease.

C825T polymorphism in the G protein beta3 subunit gene (GNB3) is associated with increased transmembrane signal transduction via adenylyl cyclase inhibiting G (G(i)) proteins. We tested whether GNB3 C825T is associated with an increased risk of coronary artery disease (CAD). Genotypes were determined with polymerase chain reaction and allele-specific fluorogenic probes. Angiographically examined, consecutive patients (n=998) with CAD and angiographically examined, sex- and age-matched controls (n=340) with no evidence of CAD were studied. The proportion of T allele carriers was significantly higher in the group with CAD compared with the control group (55.6 vs. 48.5; P=0.02). T allele carriage was associated with a 33% increase in the unadjusted risk (OR 1.33 [95% confidence interval, 1.04-1.70]) and a 37% increase in the adjusted risk (OR from the multivariate model 1.37 [95% CI, 1.06-1.76]) for CAD. Moreover, an increase in T allele carriage was associated with an increase in disease severity (P=0.006; test for trend). The strongest association was observed between T allele carriage and three-vessel disease (unadjusted OR 1.47 [95% CI, 1.10-1.96]). Thus, carrying this allele is associated with the presence as well as the severity of CAD

ABO locus O1 allele and risk of myocardial infarction.

An association between ABO blood group and myocardial infarction (MI) has been described. One probable mechanism underlying this association is the influence of ABO blood group on plasma von Willebrand factor (vWF) levels. We conducted this genetic study to test whether the ABO O1 allele is associated with low vWF plasma levels and with a reduced risk of MI. Cases consisted of 793 consecutive, angiographically examined patients with either acute or prior MI. As controls served 340 angiographically examined patients with neither coronary artery disease nor signs of MI. ABO1 locus alleles (A1, A2, B, O1, O2) were identified with polymerase chain reaction and fluorogenic probes. The distribution of O1 alleles in the MI group versus the control group was: no O1 allele (15.4%/10.0%), one O1 allele (49.7%/50.0%) and two O1 alleles (34.9%/40.0%) (P = 0.035). O1 allele carriage was associated with a 39% reduction in the risk of MI unadjusted odds ratio, 0.61; 95% confidence interval, 0.41-0.91). The significant association was maintained after adjustment for other cardiovascular risk factors. vWF antigen levels correlated with the number of O1 alleles (P = 0.00003) in a separate control group (n = 164). Carriage of the O1 allele is associated with a decreased risk of myocardial infarction, with homozygosity providing the greatest protection