Balkan Journal of Medical Genetics

ASSOCIATION OF CYP2C19*2 C.681G>A (RS4244285) LOSS-OF-FUNCTION ALLELE WITH CARDIOVASCULAR DISEASE RISK IN THE KOSOVO POPULATION
Elshani N1*, Ukella K1, Staninova Stojovska M2, Naumovska Z2, Kurshumliu M3, Gorani D4, Kapedanovska Nestorovska A
*Corresponding Author: Corresponding Author: Nora Elshani, Glloku te Shelgjet “Veternik” 10000-Prishtinë, Kosova. Phone: +38344601032. E-mail: nora.elshani1@gmail.com; nora.elshani@rezonanca-rks.com.
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INTRODUCTION

Clopidogrel remains a cornerstone in dual antiplatelet therapy for reducing the risk of cardiovascular events in patients with coronary artery disease (CAD), as well as those undergoing percutaneous coronary interventions (PCI). It is particularly beneficial in preventing thrombotic events in patients at risk for or who have experienced acute coronary syndromes (ACS), including myocardial infarction (MI) with or without ST-elevation (STEMI or NSTEMI) or unstable angina [1]. Clinical trials (such as CAPRIE, PLATO, CLARITY-TIMI 28, COMMIT/CCS- 2), have consistently demonstrated clopidogrel’s efficacy in various settings, including in secondary prevention and acute coronary syndromes. However, these clinical trials also emphasize the emergence of newer antiplatelet agents, such as prasugrel and ticagrelor that may demonstrate superior efficacy in certain clinical scenarios, challenging the traditional use of clopidogrel in some patient groups [2]. Clopidogrel is the only irreversible P2Y12 (purinergic P2Y, G-protein coupled 12) inhibitor to have a class I indication in patients with stable CAD undergoing stent implantation and is recommended in those with a contrain- dication to ticagrelor or prasugrel or those taking an oral anticoagulant [3]. Despite its proven benefits, clopidogrel’s effectiveness as a prodrug is influenced by genetic and non- genetic factors, with genetic variations in the CYP2C19 gene being a key determinant of its therapeutic outcomes. CYP2C19 genetic variants, particularly loss-of-function (LOF) alleles like *2, *3, *4, and *5, have been shown to affect clopidogrel metabolism significantly. Individuals carrying two LOF-alleles exhibit reduced enzyme activity, leading to lower levels of the active metabolite and dimin- ished antiplatelet effects. This reduction in efficacy has been associated with a 2-4 fold increased risk of ischemic events, stent thrombosis, and major cardiovascular and cerebrovascular events, particularly in high-risk patient populations [4-9]. As a result, genotype-guided clopidogrel therapy has gained attention, with clinical guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) recommending its consideration, especially for patients with CAD or those undergoing PCI [10-13]. Despite promising results from studies, such as from the POPular Genetics trial [12], conflicting findings from other studies (such as CURE, TRITON-TIMI 38, EAST-AFNET 4, GRAVITAS, ISAR-REACT 5) have raised concerns about the generalizability of genotype- guided therapy [14]. These inconsistencies in the evidence contribute to the challenges in achieving widespread adop- tion of routine CYP2C19 testing. The uncertainty sur- rounding the benefits of genotype-guided therapy has led to divergent recommendations from regulatory bodies, professional societies and pharmacogenetics consortia [14- 16]. For example, The U.S. Food and Drug Administra- tion (FDA) highlights reduced clopidogrel effectiveness in individuals with CYP2C19 LOF-alleles and suggests alternative therapies for poor metabolizers, whereas the European Medicines Agency (EMA) adopts a more cau- tious approach, advising against co-administration with CYP2C19 inhibitors but not mandating genetic testing [3]. Similarly, pharmacogenetic guidelines, such as those from the Clinical Pharmacogenetics Implementation Con- sortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG), recommend CYP2C19 genotype-guid- ed antiplatelet therapy, particularly in specific high-risk populations, but these recommendations differ in certain aspects and have not been universally integrated into clini- cal practice [3, 17, 18]. The ESC’s 2020 guidelines for ACS management propose genotype-guided therapy as an alternative to standard dual antiplatelet therapy with prasugrel or ticagrelor but refrain from endorsing routine testing for all PCI patients due to limited evidence. The AHA also calls for more research to establish the role of genotyping in improving clinical outcomes, particularly for ACS patients and secondary stroke prevention. In addition to CYP2C19, other genetic polymor- phisms such as those in CES1, PON1, ABCB1, and P2RY12 also influence clopidogrel’s pharmacokinetics and phar- macodynamics by affecting drug absorption, metabolism, and platelet receptor activity and further complicating the variability in clopidogrel response [19, 20]. Non-genetic factors, including age, comorbidities (e.g., chronic kidney disease and diabetes mellitus), and drug interactions (co- administration of medications that act as CYP2C19 sub- strates, inhibitors, or inducers) also play a significant role in modulating drug efficacy [21, 22]. Beyond cardiovascu- lar outcomes, CYP2C19*2 variants have been associated with altered susceptibility to gastrointestinal disorders, such as peptic ulcers and gastroesophageal reflux disease, as well as certain neurological conditions, highlighting their multifaceted impact [21, 23, 24]. Inter-ethnic variabil- ity in the distribution of CYP2C19 genotypes adds another layer of complexity. Certain alleles, such as CYP2C19*2, are more prevalent in specific populations, with significant differences observed across ethnic groups [25, 26]. The lack of comprehensive data on the intra-ethnic distribu- tion of CYP2C19 variants, coupled with challenges such as cost-effectiveness, logistical barriers, and limitations in the local healthcare infrastructure, restrict integration of PGx testing into routine clinical practice, particularly in resource-limited or under-researched settings like Kosovo, where the integration of genetic testing into routine clinical practice remains an ongoing problem. This study aims to assess the frequency of the CY- P2C19*2 genotype in clopidogrel-treated patients with cardiovascular disease indications (CVDI) in Kosovo and evaluate its association with major adverse cardiovascular events (MACE), including cardiovascular death, nonfa- tal myocardial infarction, stroke, stent thrombosis, and revascularization.

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