Prevalence of CYP2C19 Genetic Polymorphisms Among Egyptian Patients Receiving Clopidogrel Following PCI

Background and Rationale

Percutaneous coronary intervention (PCI) is a widely used procedure for the treatment of coronary artery disease. Following PCI, dual antiplatelet therapy (DAPT), typically consisting of aspirin and a P2Y12 receptor inhibitor, is used to reduce thrombotic complications, including myocardial infarction and stent thrombosis. Clopidogrel remains a commonly prescribed P2Y12 inhibitor in patients undergoing PCI.

Clopidogrel is a prodrug that requires metabolic activation to produce its active antiplatelet metabolite. The CYP2C19 enzyme plays a major role in this process. Genetic polymorphisms in CYP2C19 can influence enzyme activity, clopidogrel activation, and the resulting antiplatelet response. The CYP2C192 (rs4244285) and CYP2C193 (rs4986893) alleles are associated with reduced or absent enzyme function, whereas CYP2C19*17 (rs12248560) is associated with increased enzyme expression or activity. The presence of reduced-function alleles may contribute to inadequate platelet inhibition and an increased risk of ischemic events in some patients receiving clopidogrel.

CYP2C19 allele frequencies vary among populations. However, data describing the prevalence of these variants, predicted metabolizer phenotypes, and their potential associations with clinical outcomes in Egyptian patients undergoing PCI remain limited. A multicenter study across Egypt may provide valuable population-specific pharmacogenetic information and help inform future research into genotype-guided antiplatelet therapy.

Study Objectives

Primary Objective

To determine the prevalence of CYP2C192, CYP2C193, and CYP2C19*17 genetic variants among Egyptian adults receiving clopidogrel following PCI.

Secondary Objectives

To characterize CYP2C19 genotype distributions and predicted metabolizer phenotypes among the study participants.

To investigate associations between CYP2C19 genetic variants and participants' demographic characteristics, cardiovascular presentation, comorbidities, and medication use.

To evaluate the potential associations between CYP2C19 genotypes or predicted metabolizer phenotypes and clinical outcomes following PCI, including ischemic events, bleeding, and hospitalization.

To generate multicenter Egyptian data that may inform future pharmacogenetic research and the development of personalized antiplatelet treatment strategies.

Study Design and Setting

This is a prospective, observational, multicenter cohort study involving approximately 1,000 adult Egyptian patients recruited from cardiac catheterization centers across Egypt. Eligible participants will be patients aged 18 years or older undergoing PCI and receiving clopidogrel as part of antiplatelet therapy.

The study will include patients undergoing PCI in the setting of acute coronary syndromes, including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina. Other clinical presentations or indications for PCI will be documented as specified in the study protocol and eligibility criteria.

The study will not randomize participants to treatment groups or assign antiplatelet therapy. Clinical management will remain the responsibility of the treating healthcare team.

Study Procedures

After eligibility has been assessed and the applicable consent procedures have been completed, demographic and clinical information will be collected using a standardized data collection form.

Approximately 3 mL of peripheral venous blood will be collected in an EDTA-containing tube for genetic analysis. Each specimen will be labeled with a unique study code to protect participant confidentiality. Samples will be stored at approximately -20°C and transported to the designated molecular laboratory in an appropriate insulated transport container under the study's specimen-handling procedures.

Genomic DNA will be extracted from the blood samples. DNA quality will be assessed before genotyping. TaqMan single-nucleotide polymorphism (SNP) genotyping using real-time polymerase chain reaction (PCR) will be performed to identify the selected CYP2C19 variants.

The genetic analysis will include:

CYP2C19*2 (rs4244285) CYP2C19*3 (rs4986893) CYP2C19*17 (rs12248560)

Genotype results will be used to characterize allele and genotype frequencies and, where supported by the available genotype information and an appropriate standardized classification system, to assign predicted CYP2C19 metabolizer phenotypes.

Data Collection

The following information will be collected where applicable and available.

1. Demographic and Anthropometric Characteristics Age Sex Height and weight Smoking status
2. Cardiovascular Presentation and PCI Characteristics Clinical presentation, including STEMI, NSTEMI, unstable angina, and other documented coronary syndromes Indication for PCI Acute coronary syndrome or chronic coronary syndrome status, as applicable Stent implantation and relevant procedural characteristics
3. Medical History and Comorbidities Diabetes mellitus Hypertension Dyslipidemia Previous myocardial infarction Previous PCI Previous coronary artery bypass grafting (CABG) Other previous coronary revascularization Heart failure Stroke or transient ischemic attack (TIA) Peripheral vascular disease Chronic kidney disease Chronic liver disease Atrial fibrillation History of gastrointestinal or intracranial hemorrhage Active cancer
4. Concomitant Medications

Medication data will include the use of aspirin, statins, beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and oral anticoagulants. Other clinically relevant medications may be recorded according to the study protocol.

Clinical Outcomes

Clinical outcomes occurring after PCI will be recorded according to the study's prespecified definitions and follow-up procedures. The outcomes of interest include the following categories.

1. Ischemic and Cardiovascular Outcomes Major adverse cardiovascular events (MACE), according to the study's prespecified definition Cardiovascular death All-cause mortality Myocardial infarction Stent thrombosis, including definite or probable stent thrombosis where ascertainable Target-vessel revascularization Target-lesion revascularization Repeat PCI CABG Stroke or TIA Recurrent angina
2. Bleeding Outcomes Major bleeding Minor bleeding Bleeding events will be classified according to the definitions specified in the study protocol.
3. Hospitalization Outcomes

Hospitalization for heart failure Hospitalization for recurrent acute coronary syndrome Bleeding-related hospitalization Other cardiovascular-related hospitalization

The ascertainment and classification of clinical outcomes will follow the available clinical documentation and the study's predefined outcome criteria.

Genetic and Statistical Analysis

Allele and genotype frequencies will be calculated for CYP2C19*2, CYP2C19*3, and CYP2C19*17. Predicted metabolizer phenotype distributions will be described using an appropriate standardized genotype-to-phenotype translation framework.

Descriptive statistical methods will summarize demographic characteristics, clinical presentation, comorbidities, medication use, genetic findings, and clinical outcomes. Associations between genetic variants or predicted metabolizer phenotypes and participant characteristics will be evaluated using appropriate statistical tests.

Where the number of observed events and the available data permit, regression or other suitable multivariable analyses will be used to investigate associations between CYP2C19 genetic findings and clinical outcomes. Potential confounding factors will be considered in the analysis. Effect estimates will be reported with appropriate measures of uncertainty, such as confidence intervals, where applicable.

The analysis will account for the observational nature of the study. Associations will not be interpreted as proof that a genetic variant directly causes a clinical outcome. The adequacy of the data for individual outcome analyses will depend on the number of observed events and the completeness of follow-up.