Saudi Cultural Missions Theses & Dissertations
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Item Restricted A COMPREHENSIVE GENOMIC INVESTIGATION FOR CLOPIDOGREL-TREATED PATIENTS UTILIZING REAL-WORLD DATA(Saudi Digital Library, 2025) Alsaeed, Maryam; Cavallari, LarisaClopidogrel is a prodrug that requires biotransformation through two sequential oxidative steps. CYP2C19 genotype is a significant determinant of inter-individual variability, as it codes for the enzyme that contributes to both oxidative steps involved in producing the active thiol metabolite. Clopidogrel-treated individuals with at least one CYP2C19 no-function allele as a genetic variant associated with poor clopidogrel response, have higher platelet reactivity and adverse cardiovascular events than those with a normal genotype. Other clinical factors, such as age, body mass index, chronic kidney disease, and diabetes, also affect the effectiveness of clopidogrel. In this dissertation, we evaluated different prediction approaches for clopidogrel effectiveness: a combined clinical-genetic score (ABCD-GENE), a clinical-only score (ABCD), a genetic-only score (GENE), and a composite rule (ABCD-OR-GENE). We examined each score’s association with major adverse cardiovascular events (MACE) among clopidogrel-treated patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) and among clopidogrel-treated patients with ischemic stroke or transient ischemic attack (TIA). Then, we sought to identify novel variants associated with MACE in ACS/PCI patients using two independent cohorts: the Precision PCI registry and the All of Us Research Program. A total of 4,739 adults with ACS and/or post-PCI and 611 ischemic stroke or TIA participants were included. Around 35% of ACS/PCI patients and 47% of ischemic stroke patients were female, and about 20% were self-reported Black in all cohorts. Kaplan-Meier analysis, Cox proportional hazard models, C-index, comparative performance, and logistic regression were utilized as appropriate. The ABCD-GENE score provided a modest, statistically significant NRI improvement over the ABCD (MD 0.14; 95% CI 0.13–0.42) and GENE (MD 0.07; 95% CI 0.00–0.13) scores, with high heterogeneity (I² = 80–91%). However, there was no significant difference between the ABCD-GENE versus the combined ABCD-OR-GENE model (MD −0.06; 95% CI −0.11 to −0.01; I² = 0%), indicating no added benefit of the latter for ACS/PCI patients. In the ischemic stroke cohort, only the ABCD-GENE (adjusted HR 0.36 [95% CI 0.14–0.93; P=0.035]) and GENE (adjusted HR 0.40 [0.18–0.85; P=0.018]) scores were linked to lower recurrent stroke risk, but in the opposite direction from what would be expected, indicating a type I error; the ABCD and ABCD-OR-GENE scores showed no significant association with recurrent stroke or TIA. In our GWAS, we identified DCTN5 as a potential candidate marker for targeted therapy in ACS/PCI patients.21 0