Pharmacogenetic analysis for the estimation of safety and efficacy in the response to clopidogrel in patients with acute coronary syndrome treated at MEDERI

Clopidogrel is an antiplatelet drug that inhibits clot formation in patients with coronary heart disease, peripheral vascular disease, and cerebrovascular disease. It works by irreversibly inhibiting P2Y, a chemoreceptor of adenosine diphosphate (ADP) (1). It has been described that multiple factors modify the pharmacokinetic and pharmacodynamic characteristics of the drug, which impacts on the clinical response of the drug(2). A great deal of interindividual variability has been identified in the therapeutic outcome among patients with the same pharmacological management scheme, which leads fundamentally to a decrease in the desired antithrombotic effect(3) . Part of the variability of the response is due to the genotype of the patient, who may be a carrier of variants in genes related to Clopidogrel metabolism. From this perspective, the involvement of CYP2C19 is relevant since it is the enzyme responsible for the biotransformation of the drug to its active metabolite. Some variants in the CYP2C19 gene generate alleles of loss or gain of function that affect the anti-platelet effect of Clopidogrel (4) . The variants CYP2C19*2 and *3 have been associated with high platelet reactivity and adverse cardiovascular events (5, 6), while the CYP2C19*17 allele increases enzymatic activity related to increased platelet inhibition associated with increased risk of bleeding (7). The frequency of alleles of susceptibility to unwanted reactions in platelet treatment is different depending on the ethnic origin of the study population. Thus, alleles with loss of function occur in about 30% of the Asian population and 15% of Caucasians and Africans. The frequency of gain of function alleles is estimated to be 3-21% (5, 8). The European Medicines Agency (EMEA) reported that about 86% of patients treated with clopidogrel had at least one adverse reaction and 40.4% corresponded to a serious adverse event. The incidence of death as a result of ADRs was about 4.1% (EMEA 2004). The high incidence of ADR and the mortality associated with clopidogrel use suggests the need to study potential genetic and non-genetic factors predictive of unwanted therapeutic effects. Some previous studies have addressed the analysis of the involvement of CYP2C19 in the therapeutic response. However, few variants have been evaluated, so that the implication of the variability of the entire coding and promoting region of the CYP2C19 gene in the potential efficacy and safety of clopidogrel treatment is not currently known with precision. The knowledge gap in the Colombian population makes it essential to address the search for potential molecular markers from a pharmacogenetic perspective, that is, from the study of genetic variants that are related to individual differences in response to drugs. From this perspective, the sequencing of the region and coding of the gene of greatest impact on drug metabolism (CYP2C19) will allow the definition of the association of common alleles, rare alleles, combinatorial alleles between the promoter and coding region (haplotypes) on the potential response to therapy. The association of genetic variants with non-genetic factors will establish an algorithm potentially applicable to the Colombian population, leading to the potential application in the identification of patients at risk of developing adverse reactions or therapeutic failures.
Additionally, we propose to perform validations through in vitro functional analysis of the impact of some genetic variants identified in the promoter and/or coding region of the CYP2C gene19 . This represents a valuable contribution since there is currently a gap in the functional characterization of genetic variants of clinical interest in a gene that, like CYP2C19, is responsible for the phase I metabolism of a significant number of drugs, including clopidogrel.

Adverse drug reactions (ADRs), Haplotypes, Single nucleotide polymorphisms (SNPs), Platelet aggregation, Acute coronary syndrome.

The development of this research project will allow the training of 1 student from the Internal Medicine residency of the School of Medicine and Health Sciences program. In addition, 3 undergraduate medical students from the School of Medicine and Health Sciences attached to the research elective at CIGGUR and 1 undergraduate medical student from the School of Medicine and Health Sciences belonging to the CIGGUR Research Seedbed are actively working on the project.