Platelet pharmacogenomics

Abstract

Summary. Platelet responsiveness to conventional antiplatelet therapy underlies a high interindividual variability influenced by various factors. For instance, antiplatelet therapy does not curtail the expected effects in a relevant number of patients as demonstrated by the occurrence of repeated cardiovascular events including stent thrombosis and/or by inadequate platelet inhibition measured by in vitro platelet function assays. Besides non-genetic factors such as age, gender, liver and renal function and co-medication, considerable variation of antiplatelet drug responsiveness can be attributed to genetic factors including polymorphisms and genetic variants of platelet surface proteins and drug metabolizing enzymes. Nowadays, platelet pharmacogenomics has started a new field with the goal to link genetic information of various drug targets to interindividual variability of drug response. Evolving data from large cohort studies suggest a promising role for pharmacogenomics in the context of antiplatelet therapy. Additionally, with the revolution of low cost and high-throughput genotyping techniques, genetic testing has become affordable for clinical application and individualization of therapy. However, a key issue to define the future role of pharmacogenomics will rely on the benefit and the timeliness of implementing the genetic information into therapeutic decision. Hence, it warrants further investigations to document the prognostic effects of therapeutic alterations in distinct genotypes. Concerning the safety profile of emerging antiplatelet and antithrombotic drugs in certain risk groups it would be fatal to individualize treatment barely on behalf of an atherothrombotic genotype. In contrast, individual risk assessment combining non-genetic information and pharmacogenetic analysis represents a reasonable concept. Here, we provide a review on current data describing the role of pharmacogenomics in the field of antiplatelet drug treatment in cardiovascular patients with future directions.

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

“…Besides CYP2C19 [157][158][159], polymorphisms of ABCB1 have been sought to explain the inter-individual variability [160,161]. Two studies reported lower plasma clopidogrel concentrations in subjects with the 3435TT genotype [160,162].…”

Data collection as a barrier to personalized medicine

“…Yet, this combination fails to prevent ischemic events in most treated patients, and both drugs cause bleeding. Given that clopidogrel is a prodrug oxidized to the active metabolite by cytochrome P450s and that the most significant of these enzymes (CYP2C19) [5] has multiple loss-of-function alleles (http://www.cypalleles.ki.se/cyp2c19.htm), it was proposed that the CYP2C19 genotype would predict efficacy and enable individualized dosing to maximize efficacy while minimizing adverse effects. However, clinical testing of these ideas yielded nonreplicable results [6,7].…”

Clopidogrel Pharmacogenetics

“…Вторая группа -гены семейства цитохрома Р-450 (CYP2C19, CYP2C9, CYP3A4, CYP3A5), через которые идет метаболизм кло-пидогрела. Третья группа -гены, определяющие фар-макодинамику клопидогрела -гены, кодирующие рецепторы тромбоцитов P2Y12, GPIIIa [11].…”