Genetic polymorphisms of the platelet receptors P2Y12, P2Y1 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: 2.45). 02/2007; 119(3):355-60. DOI: 10.1016/j.thromres.2006.02.006
Source: PubMed


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.

4 Reads
  • Source
    • "Platelet surface glycoprotein IIIa (ITGB3) haplotype P1A1/P1A2 (807C > T, rs1126643) has been shown to have an effect on sensitivity to aspirin (Nurden 1997 ; Undas et al. 1999 ). Some of these results could not be confi rmed for aspirin and clopidogrel in the later studies (Pamukcu et al. 2005 ; Lev et al. 2007 ). Loss-of-function variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators of clopidogrel response. "
    [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 (MiniƱo 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
  • Source
    • "Although the polymorphisms in most platelet itself genes are not necessarily related with platelet hyperreactivity, there are still other forms of genetic polymorphisms that associated with platelet hyperreactivity, which have been considered to be the intrinsic factors of antiplatelet agents " resistance " , e.g. aspirin resistance [8] [9] [10] [11] and clopidogrel resistance [12] [13] [14] [15]. In contrast, 'environmental' factors including pathologic state such as hyperlipoidemia, hypertension, diabetes and lifestyle have been proved intensively associated with platelet hyperreactivity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Platelets play a key role in thrombosis and haemostasis, which can be either beneficial or deleterious depending on the circumstance. Antiplatelet therapy is the 'cornerstone' in the prevention and treatment of thrombotic diseases. Platelet activation is a complex process known as transmembrane signaling which then serves to activate the platelet via a cascade of biochemical interactions. Currently available strategies of antiplatelet therapy are generally based on the signaling pathway of platelet activation, which possess the characters that mono-agent, mono-target, and mainly irreversible inhibition. Therefore, both established and novel antiplatelet agents have their own pros and cons and such problems as resistance, drug-drug interaction, discontinuation and monitoring, etc. have been appeared. Due to the problems existing in current antiplatelet agents, future new strategies for antiplatelet targets, agent-developing and treatment might probably include three aspects: targeting the factors associated with platelet hyperactivity, developing novel antiplatelet agents with multiple targets, mild and reversible properties from natural products, and keeping healthy lifestyle and emphasizing prevention.
    Thrombosis Research 07/2008; 123(1):35-49. DOI:10.1016/j.thromres.2008.05.003 · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antiplatelet therapies are often used to minimise complications in patients with acute coronary syndromes or who are undergoing percutaneous coronary intervention with stenting. However, the occurrence of 'high on-treatment platelet reactivity' associated with the gold standard treatments aspirin and clopidogrel in a subset of individuals limits the efficacy of these drugs. This lack of response, which has been attributed to a genetic polymorphism, is associated with an increased risk of subsequent atherothrombotic events. In recent years, platelet function assays have been used to monitor antiplatelet inhibition. Various tests have been introduced that allow physicians to evaluate pharmacological response and potentially permit risk stratification of patients. While some of these assays have proved to be labour-intensive, the development of point-of-care assays may ease the time burden in clinical practice. Preliminary findings demonstrate the effectiveness of altering therapy based on assay results in terms of improving clinical outcomes, suggesting an important role for platelet function testing in the future of antiplatelet therapy.
    Interventional Cardiology (London) 01/2010; 5(1). DOI:10.15420/icr.2010.5.1.96
Show more

Similar Publications