Pharmacogenetics in Cardiovascular Disorders
Dual antiplatelet therapy with clopidogrel and aspirin is the gold standard therapy prescribed to patients undergoing percutaneous coronary intervention (PCI), and is also used to prevent recurrent ischemic events after non-ST elevation acute coronary syndrome, together with aspirin (dual antiplatelet therapy). It is a thienopyridine inhibitor of the platelet P2Y adenosine diphosphate (ADP) receptor and prevents platelet degranulation by inhibiting the conversion of glycoprotein (GP)IIb/IIIa to the fibrinogen-binding form. When ingested, clopidogrel is an inactive pro-drug; intestinal absorption is limited by an efflux pump P-glycoprotein coded by the ABCB1 gene. The majority of the pro-drug is in fact metabolized into inactive metabolites by ubiquitous esterases. The minority is bio-activated by various CYP isoforms into active metabolites. These metabolites irreversibly antagonize the ADP receptor (coded by the P2RY12 gene), which in turn inactivates the fibrinogen receptor (the GPIIb/IIIa receptor coded by the ITGB3 gene) involved in platelet aggregation. In this way, it inhibits platelet aggregation.
The platelet response to clopidogrel is highly heritable; in fact it is a drug for which pharmacogenetics has already given strong evidence (Table 1). Inter-individual variability strongly affects the pharmacodynamic response to clopidogrel. A combination of clinical variables such as obesity, insulin resistance, and nature of the coronary event affects the way in which an individual might respond to clopidogrel treatment. Furthermore, there is growing evidence that the response to clopidogrel may be influenced by pharmacokinetic variables, such as intestinal absorption and metabolic activation in the liver, both of which are affected by genetic polymorphisms. The biotransformation to an active metabolite is mediated by a two-step CYP system-dependent oxidation.
Genes encoding the CYP enzymes are polymorphic, and several studies have demonstrated allele-specific levels of enzymatic function. The variants in these genes include gene deletions, duplications, and deleterious mutations creating inactive products. Furthermore, amino acid insertions may also change the specificity of the substrate; mutations in introns might alter splice sites; and copy number variations might result in an increase of the drug metabolism, causing normal dose treatments to be ineffective. The cytochromes involved in clopidogrel metabolism are CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5, and many groups hypothesized that loss of function mutations in the genes encoding these enzymes might be associated with drug resistance; however, evidence for only some of these has been provided. In particular, multiple studies have demonstrated a strong association between loss of function alleles of the CYP2C19 gene and response to clopidogrel (alleles *2 rs4244285, which creates an aberrant splice site and shows the strongest association; *3 rs4986893, which, together with the alleles *2 is responsible for most of the poor metabolizers; and the last two, *4 rs28399504 and *5 rs56337013, which have a frequency <1 % in all ethnicities). These variants result in resistance to clopidogrel treatment, with an increased risk of death, myocardial infarction, or stroke, especially among patients undergoing PCI. Recently, a gain of function allele *17 (rs1248560) was associated with hypersensitivity and adverse reaction to the drug, although it seems to exert a moderate effect. Several studies have also demonstrated that decreased-function variations on the CYP2C9 encoding gene may also be responsible for a pharmacodynamically poor responder phenotype in healthy subjects.
Some other gene variants have been analyzed and found to be associated with clopidogrel response, such as a polymorphism in the ABCB1 gene (ATP-binding cassette, subfamily C, member 1), encoding for an intestinal efflux transporter; and genes involved in clopidogrel metabolism such as the P2Y12 receptor and GP Ia gene (Table 1), but did not appear to have a very strong influence over clopidogrel biological efficacy. Overall, the percentage of explained heritability for platelet response to clopidogrel is only 18 % out of a total 73 %. In this case, as in many other complex genetic traits, unraveling the underlying missing heritability could be the key step to set up genetic tests that could be useful for clinical purposes.
On the other hand, as for warfarin, novel drugs might be synthesized to avoid the problem. Prasugrel and ticagrelor are newer antiplatelet drugs that could be an alternative to clopidogrel. Their effect is less variable and fewer ischemic events are associated with their use; however, more bleeding is related to the use of these drugs. Pharmacogenetic studies are currently considering these drugs. So far, no association has been found.
4 Antiplatelet Therapies: Clopidogrel, Prasugrel, and Ticagrelor
Dual antiplatelet therapy with clopidogrel and aspirin is the gold standard therapy prescribed to patients undergoing percutaneous coronary intervention (PCI), and is also used to prevent recurrent ischemic events after non-ST elevation acute coronary syndrome, together with aspirin (dual antiplatelet therapy). It is a thienopyridine inhibitor of the platelet P2Y adenosine diphosphate (ADP) receptor and prevents platelet degranulation by inhibiting the conversion of glycoprotein (GP)IIb/IIIa to the fibrinogen-binding form. When ingested, clopidogrel is an inactive pro-drug; intestinal absorption is limited by an efflux pump P-glycoprotein coded by the ABCB1 gene. The majority of the pro-drug is in fact metabolized into inactive metabolites by ubiquitous esterases. The minority is bio-activated by various CYP isoforms into active metabolites. These metabolites irreversibly antagonize the ADP receptor (coded by the P2RY12 gene), which in turn inactivates the fibrinogen receptor (the GPIIb/IIIa receptor coded by the ITGB3 gene) involved in platelet aggregation. In this way, it inhibits platelet aggregation.
The platelet response to clopidogrel is highly heritable; in fact it is a drug for which pharmacogenetics has already given strong evidence (Table 1). Inter-individual variability strongly affects the pharmacodynamic response to clopidogrel. A combination of clinical variables such as obesity, insulin resistance, and nature of the coronary event affects the way in which an individual might respond to clopidogrel treatment. Furthermore, there is growing evidence that the response to clopidogrel may be influenced by pharmacokinetic variables, such as intestinal absorption and metabolic activation in the liver, both of which are affected by genetic polymorphisms. The biotransformation to an active metabolite is mediated by a two-step CYP system-dependent oxidation.
Genes encoding the CYP enzymes are polymorphic, and several studies have demonstrated allele-specific levels of enzymatic function. The variants in these genes include gene deletions, duplications, and deleterious mutations creating inactive products. Furthermore, amino acid insertions may also change the specificity of the substrate; mutations in introns might alter splice sites; and copy number variations might result in an increase of the drug metabolism, causing normal dose treatments to be ineffective. The cytochromes involved in clopidogrel metabolism are CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5, and many groups hypothesized that loss of function mutations in the genes encoding these enzymes might be associated with drug resistance; however, evidence for only some of these has been provided. In particular, multiple studies have demonstrated a strong association between loss of function alleles of the CYP2C19 gene and response to clopidogrel (alleles *2 rs4244285, which creates an aberrant splice site and shows the strongest association; *3 rs4986893, which, together with the alleles *2 is responsible for most of the poor metabolizers; and the last two, *4 rs28399504 and *5 rs56337013, which have a frequency <1 % in all ethnicities). These variants result in resistance to clopidogrel treatment, with an increased risk of death, myocardial infarction, or stroke, especially among patients undergoing PCI. Recently, a gain of function allele *17 (rs1248560) was associated with hypersensitivity and adverse reaction to the drug, although it seems to exert a moderate effect. Several studies have also demonstrated that decreased-function variations on the CYP2C9 encoding gene may also be responsible for a pharmacodynamically poor responder phenotype in healthy subjects.
Some other gene variants have been analyzed and found to be associated with clopidogrel response, such as a polymorphism in the ABCB1 gene (ATP-binding cassette, subfamily C, member 1), encoding for an intestinal efflux transporter; and genes involved in clopidogrel metabolism such as the P2Y12 receptor and GP Ia gene (Table 1), but did not appear to have a very strong influence over clopidogrel biological efficacy. Overall, the percentage of explained heritability for platelet response to clopidogrel is only 18 % out of a total 73 %. In this case, as in many other complex genetic traits, unraveling the underlying missing heritability could be the key step to set up genetic tests that could be useful for clinical purposes.
On the other hand, as for warfarin, novel drugs might be synthesized to avoid the problem. Prasugrel and ticagrelor are newer antiplatelet drugs that could be an alternative to clopidogrel. Their effect is less variable and fewer ischemic events are associated with their use; however, more bleeding is related to the use of these drugs. Pharmacogenetic studies are currently considering these drugs. So far, no association has been found.
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