Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel.

The Methodist DeBakey Heart Center, The Methodist Hospital and Baylor College of Medicine, Section of Cardiology, 6565 Fannin St./Mail Station F-1090, Houston, TX 77030, USA.
Thrombosis Research (Impact Factor: 2.43). 02/2007; 119(3):355-60. DOI: 10.1016/j.thromres.2006.02.006
Source: PubMed

ABSTRACT There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel.
Patients (n=120) undergoing percutaneous coronary intervention who received aspirin for > or =1 week but not clopidogrel were included. Blood samples were drawn at baseline and 20-24h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or =70% and 0.5 mg/mL arachidonic acid-induced aggregation > or =20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or =10% in response to 5 and 20 microM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y(12) gene and the 1622A>G polymorphism of the P2Y(1) gene were genotyped by polymerase chain reaction.
There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2) carriers (P=0.065).
We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y(12) or P2Y(1) and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute coronary syndromes (ACS) remain life-threatening disorders, which are associated with high morbidity and mortality. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of clopidogrel. While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug–drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability, and how they are interrelated, is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence the pharmacokinetics and pharmacodynamics of clopidogrel and how they mechanistically contribute to inter-individual differences in the response to clopidogrel treatment.
    Clinical Pharmacokinetics 01/2015; 54(2). DOI:10.1007/s40262-014-0230-6 · 5.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The plasma-membrane integrin αIIbβ3 (CD41/CD61, GPIIbIIIa) is a major functional receptor in platelets during clotting. A common isoform of integrin β3, Leu33Pro is associated with enhanced platelet function and increased risk for coronary thrombosis and stroke, although these findings remain controversial. To better understand the molecular mechanisms by which this sequence variation modifies platelet function, we produced transgenic, knock-in mice expressing a Pro32Pro33 integrin β3. Consistent with reports utilizing human platelets, we found significantly reduced bleeding and clotting times, as well as increased in vivo thrombosis in Pro32Pro33 homozygous mice. These alterations paralleled increases in platelet attachment and spreading onto fibrinogen, resulting from enhanced integrin αIIbβ3 function. Activation with PAR4-AP, the main thrombin signaling receptor in mice, showed no significant difference in activation of Pro32Pro33 mice as compared to controls, suggesting that inside-out signing remains intact. However, under un-stimulated conditions, the Pro32Pro33 mutation led to elevated Src phosphorylation, facilitated by increased talin interactions with the β3 cytoplasmic domain, indicating that the αIIbβ3 intracellular domains are primed for activation while the ligand-binding domain remains unchanged. Acute dosing of animals with a Src inhibitor was sufficient to rescue the clotting phenotype in KI mice to wild-type levels. Together, our data establish that the Pro32Pro33 structural alteration modifies the function of integrin αIIbβ3, priming the integrin for outside-in signaling, ultimately leading to hypercoagulability. Furthermore, our data may support a novel approach to anti-platelet therapy by Src inhibition, where hemostasis is maintained while reducing risk for cardiovascular disease.
    Molecular pharmacology 04/2014; 85(6). DOI:10.1124/mol.114.091736 · 4.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1 Introduction Cardiovascular disease (CVD), generally called heart disease, is a very broad term that encom-passes a range of conditions that in someway affect the cardiovascular system and its normal function. Any problems with the heart and the blood vessels together constitute this category of disease. CVD is the leading cause of death spe-cifi cally in developing countries (Gaziano 2005). According to the estimates, 17 million people worldwide die of CVD every year, particularly of heart attacks and strokes. Even in developed countries like the United States, in 2008, over 616,000 individuals died of heart disease. This amounted to nearly 25 % of the total deaths in the United States that year (Miniño et al. 2011). For prevention and treatment of CVD, cardiovascular drugs are prescribed abundantly, without Abstract Cardiovascular disease (CVD), commonly known as heart disease, is the leading cause of death all over the world. Nearly one in four deaths worldwide is attributed to CVD. Generally, CVD constitutes a number of overlapping structural and functional irregularities in the heart and blood vessels, which together constitute the cardiovascular system. Given this, the corresponding drugs also either can treat or prevent these overlapping conditions. Often, more than one drug is prescribed to treat a medical condition, since one medication alone cannot remedy the problem. High mortality and morbidity due to CVD automatically requires physicians to treat CVD aggressively, leading to adverse drug reactions. Still, some patients do not respond positively even if the strongest recommended drug dosage is administered. Research in the CVD fi eld has demonstrated linkage between gene variation and the severity of diseases such as blood choles-terol level or blood pressure. Correspondingly, research over more than three decades has established the linkage of genetic variation with the effi cacy of CVD treatment in the cohorts of different CVD disease types. In this chapter, recent advances in the fi eld of cardiovascular pharmacoge-netics and pharmacogenomics are summarized.
    Omics for personalized medicine, 2013 edited by Nirmal Kumar Ganguly, Dipali Dhawan, Debmalya Barh, 10/2013: chapter Cardiovascular Disease Pharmacogenomics; Springer., ISBN: 978-8132211839