Date of Award
Doctor of Philosophy (PhD)
Bassam R. Ali
George P. Patrinos
Pharmacogenetic variations contribute to interindividual differences in drug response. Advances in molecular techniques provided insights into interpopulation pharmacogenomic variations. A limited number of pharmacogenetic studies were conducted in the UAE population. The current study aims to explore the variation landscape in important pharmacogenes in Emiratis. Furthermore, it investigates the association between VKORC1 variants and warfarin dose in cardiovascular patients. Finally, this study explores the applied/needed germline pharmacogenetic tests in oncology in the UAE. In 100 healthy Emiratis, variants and star alleles in 100 relevant pharmacogenes were defined by next-generation sequencing. 63% of detected variants were rare, 30% were novel, and 141 variants were novel and damaging. By clinical annotations, filtering variants resulted in 99 clinically actionable variants, from which 44 are highly significant alleles. Revising the results against the clinical pharmacogenetics implementation consortium guidelines demonstrated that 93% of participants have at least one actionable variant with a dosing recommendation. The effect of VKORC1 on warfarin dose was explored in 90 patients. A model built from two VKORC1 variants, rs9923231 and rs61742245, with age, significantly predicted warfarin dose. High incidence rates of adverse chemotherapy effects were reported from 66 pediatric acute lymphoblastic leukemia patients, which indicates the plausibility of pharmacogenetic research to investigate toxicity biomarkers. Few cases had a clinical pharmacogenetic test of TPMT and NUDT15 before starting oral 6-mercaptopurine. Patients who received pharmacogenetic-guided doses suffered from less adverse effects. Exploring the adverse drug effects in a group of 77 breast cancer patients was faced by deficiencies in adverse effects reporting. The reported adverse events suggested suitable candidates for future pharmacogenetic research. This research highlighted population-specific variants, unexplored adverse drug events, and possible pharmacogenomics applications in the UAE. Various research opportunities were illustrated for the scientific community.
Al Mahairi, Zeina Nizar, "PHARMACOGENOMICS IN THE EMIRATI POPULATION: APPLICATIONS IN CARDIOVASCULAR DISEASES AND ONCOLOGY" (2020). Institute of Public Health Dissertations. 3.