Pharmacogenetics of Antiplatelet Drugs

Abstract

Pharmacogenetics refers to the genetic factors that influence the response to a drug, often involving genetic variations in drug metabolizing enzymes. The pharmacogenetics of antiplatelet agents is in its infancy and largely reflects variations in drug targets or related genes. One particular gene variant, the Pl A2 polymorphism of the glycoprotein (GP) IIb/IIIa receptor, is now emerging as a probable determinant of the response to antiplatelet agents including GPIIb/IIIa antagonists. This variant may in part explain the heterogeneity in the response to GPIIb/IIIa antagonists. The Pl A2 genotype appears to be associated with an adverse outcome in patients treated with an oral GPIIb/IIIa antagonist and may be a factor in the observed failure of these agents in unselected populations. However, there are preliminary indications that other antiplatelet agents may have an enhanced effect in Pl A2 subjects. Further clinical trials in particular are required to definitively characterize the pharmacogenetic effect of Pl A2. Other polymorphisms are also likely to contribute to the pharmacogenetics of antiplatelet agents, but these await investigation. KEY WORDS: pharmacogenetics, Pl A2, GPIIb/IIIa receptor, aspirin, dipyridamole, clopidogrel, GPIIb/IIIa antagonists DOMAINS: thrombosis, pharmacogenomics INTRODUCTIONAge, concurrent medications, and renal and liver dysfunction are well-characterized factors that can affect the efficacy or toxicity of drug treatment. Inherited factors are also emerging as determinants of the pharmacokinetics and pharmacodynamics of many medications. Pharmacogenetics is that field of science concerned with this hereditary component of drug response. Variations in genes that encode proteins involved in drug metabolism can be important determinants of a patient's response to therapy. Genetic variations in many drug metabolizing enzymes and their phenotypes have been characterized [1]. However, genetic variation in drug transporters and drug targets, as well as genetic heterogeneity underlying the disease being treated, can also modulate response to medications. Curtin and Fitzgerald: Pharmacogenetics of Antiplatelet Drugs TheScientificWorldJOURNAL (2002) 2, 791-800 792Initially, identification of inherited differences in drug metabolism was based on observations in patients who suffered adverse effects despite being treated with standard doses of a drug [2]. However the focus of research in pharmacogenetics, triggered in part by the human genome project, has shifted to identification of single nucleotide polymorphisms (SNPs) in target genes. Drug trials or disease cohorts provide an opportunity to determine whether such SNPs modify drug response. For example, a variant of the β 2 adrenergic receptor enhances the response to β-agonist therapy in asthmatics, as the receptor fails to desensitize [3]. Variants in genes that may not be targets for drugs but are involved in the disease may also influence drug response. For example, recent evidence suggests that the angiotensin converting enzyme...

Epidemiology of Atherothrombotic Disease and the Effectiveness and Risks of Antiplatelet Therapy

“…Additionally, patients who have the P 1 A 2 genotype also experience more adverse outcomes when treated with oral GP IIb/IIIa antagonists. 57 However, a recent metaanalysis of 191 studies did not confirm the relationship between P 1 A 2 and CHD (OR: 1.03; 95% CI: 0.98 -1.07). 58 Another well-studied platelet receptor polymorphism is the GP Ib␣ 5C allele.…”

“…58 Receptor polymorphisms, genetic differences in hepatic metabolism, as well as occult genetic polymorphisms in platelet aggregation and coagulation function, are likely to account for a number of other variations in response to both antiplatelet and antithrombotic therapies among different ethnic groups. 48,57 However, the current limited availability of data concerning the frequency of different platelet receptor polymorphisms makes it difficult to make meaningful conclusions about the impact of these polymorphisms in different populations.…”