Date of Defense
6-11-2024 12:00 PM
Location
Yanah Theatre
Document Type
Dissertation Defense
Degree Name
Doctor of Philosophy in Biomedical Sciences
College
CMHS
First Advisor
Prof. Bassam R. Ali
Keywords
Pharmacogenomics implementation, Anti-platelets, Clopidogrel, Acute coronary syndrome, Genetic variants, United Arab Emirates population.
Abstract
Anti-platelet therapy is a cornerstone in the management of cardiovascular diseases such as acute coronary syndrome (ACS) and stroke. These medications are essential for reducing the risk of thrombotic events by preventing platelet aggregation. However, variations in cardiovascular pharmacogenes can significantly impact the metabolism, efficacy, and safety of anti-platelet therapies, making personalized medicine increasingly important for optimizing treatment outcomes. Pharmacogenomic testing has emerged as a crucial tool in tailoring anti-platelet therapy, particularly for patients with subtherapeutic responses due to genetic factors. While extensive research has been conducted globally to identify and study the effect of the pharmacogenomic variants that influence anti-platelet management, interest in this area within the United Arab Emirates (UAE) is relatively new. Studies on pharmacogenomic variants specific to the Emirati population are still in their infancy and remain limited.
In this current study, whole exome sequencing data from 298 healthy Emirati individuals were analyzed to investigate the key pharmacogenes, variants, haplotypes, and diplotypes known to affect the pharmacokinetics of clopidogrel, which could influence its efficacy. The analysis revealed a high frequency of the 11 actionable variants in several pharamcogenes, including cytochrome P-450 (CYP2C19), ATP-binding cassette subfamily B member 1 (ABCB1), Paraoxonase-1 (PON1), and the purinergic receptor (P2Y12R). These variants are known to impact clopidogrel metabolism and response.
Further, in this thesis, I describe the first prospective randomized controlled trial (RCT) conducted in the UAE to evaluate the impact of pharmacogenomic testing for five actionable CYP2C19 variants in 169 anti-platelet users with acute coronary syndrome. The results demonstrated a 10% improvement in clopidogrel efficacy, reducing the clinical risk of subsequent cardiovascular complications. Nevertheless, incorporating pharmacogenomic testing did not significantly mitigate the adverse outcomes of anti-platelet therapy (bleeding outcomes) (P-value >0.05). One explanation for this is that ticagrelor, the safer anti-platelet for patients with impaired CYP2C19metabolism, is known to be associated with a higher risk of bleeding compared to clopidogrel.
Additionally, a retrospective cohort study was conducted in this research to examine the association of three ABCB1 variants—rs1045642 (C3435T), rs2032582 (G2677T), and rs1128503 (C123T)—with major adverse cardiovascular events (MACE) in 174 ACS patients. Despite the high prevalence of the mutant alleles in the multiethnic UAE population (48.85%, 50%, and 51.03%, respectively), these variants did not significantly affect the risk of thrombotic complications in patients with a history of myocardial infarction (P>0.05).
This research highlights the critical pharmacogenes impacting clopidogrel efficacy, UAE-specific genetic variants, unexplored adverse events and complications, and the potential for broader pharmacogenomic implementation in the UAE healthcare system. These findings open the door for future research opportunities and contribute valuable insights to the local and global scientific communities.
Included in
GENOMICS INSIGHTS INTO ANTI-PLATELETS THERAPY: UNRAVELING OF VARIANTS AND THE IMPLEMENTATION OF CLOPIDOGREL-GUIDED THERAPY IN THE UNITED ARAB EMIRATES
Yanah Theatre
Anti-platelet therapy is a cornerstone in the management of cardiovascular diseases such as acute coronary syndrome (ACS) and stroke. These medications are essential for reducing the risk of thrombotic events by preventing platelet aggregation. However, variations in cardiovascular pharmacogenes can significantly impact the metabolism, efficacy, and safety of anti-platelet therapies, making personalized medicine increasingly important for optimizing treatment outcomes. Pharmacogenomic testing has emerged as a crucial tool in tailoring anti-platelet therapy, particularly for patients with subtherapeutic responses due to genetic factors. While extensive research has been conducted globally to identify and study the effect of the pharmacogenomic variants that influence anti-platelet management, interest in this area within the United Arab Emirates (UAE) is relatively new. Studies on pharmacogenomic variants specific to the Emirati population are still in their infancy and remain limited.
In this current study, whole exome sequencing data from 298 healthy Emirati individuals were analyzed to investigate the key pharmacogenes, variants, haplotypes, and diplotypes known to affect the pharmacokinetics of clopidogrel, which could influence its efficacy. The analysis revealed a high frequency of the 11 actionable variants in several pharamcogenes, including cytochrome P-450 (CYP2C19), ATP-binding cassette subfamily B member 1 (ABCB1), Paraoxonase-1 (PON1), and the purinergic receptor (P2Y12R). These variants are known to impact clopidogrel metabolism and response.
Further, in this thesis, I describe the first prospective randomized controlled trial (RCT) conducted in the UAE to evaluate the impact of pharmacogenomic testing for five actionable CYP2C19 variants in 169 anti-platelet users with acute coronary syndrome. The results demonstrated a 10% improvement in clopidogrel efficacy, reducing the clinical risk of subsequent cardiovascular complications. Nevertheless, incorporating pharmacogenomic testing did not significantly mitigate the adverse outcomes of anti-platelet therapy (bleeding outcomes) (P-value >0.05). One explanation for this is that ticagrelor, the safer anti-platelet for patients with impaired CYP2C19metabolism, is known to be associated with a higher risk of bleeding compared to clopidogrel.
Additionally, a retrospective cohort study was conducted in this research to examine the association of three ABCB1 variants—rs1045642 (C3435T), rs2032582 (G2677T), and rs1128503 (C123T)—with major adverse cardiovascular events (MACE) in 174 ACS patients. Despite the high prevalence of the mutant alleles in the multiethnic UAE population (48.85%, 50%, and 51.03%, respectively), these variants did not significantly affect the risk of thrombotic complications in patients with a history of myocardial infarction (P>0.05).
This research highlights the critical pharmacogenes impacting clopidogrel efficacy, UAE-specific genetic variants, unexplored adverse events and complications, and the potential for broader pharmacogenomic implementation in the UAE healthcare system. These findings open the door for future research opportunities and contribute valuable insights to the local and global scientific communities.