Saudi Cultural Missions Theses & Dissertations
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Item Restricted Integrative Genomic Analysis of Cytogenetically Normal Acute Myeloid Leukaemia(University College London, 2025) Alhawaj, Ali Fouad; Mansour, MarcAcute Myeloid Leukaemia (AML) is a haematological malignancy characterized by increased proliferation and blocked differentiation of haematopoietic progenitors. Cytogenetically normal AML (CN-AML) accounts for approximately 50% of all AML cases, with a 5-year survival rate of approximately 50%. Approximately 40% of patients exhibit primary resistance to induction chemotherapy; however, the molecular basis remains poorly understood. Additionally, high SETBP1 expression has been implicated in AML development, although the underlying mechanism remains unclear. This thesis aimed to explore the genomic and transcriptomic profiles of primary-resistant CN-AML in adults, and SETBP1 allele-specific expression (ASE) as a potential cause of high SETBP1 expression. Through whole-exome and RNA sequencing of resistant and matched remission samples, we identified a high presence of UBTF-TD in CN-AML (12%) and a higher incidence of WT1 mutations in the resistant versus remission cohorts (29% vs. 10%, p=0.005). However, CRISPR knockout of WT1 in a 416B mouse model did not confer resistance to Cytarabine or Daunorubicin RNA sequencing indicated enrichment of senescence signatures in the resistant cohort, along with novel gene fusions of LATS2-ZMYM2 (20.9%) and LATS2-HMGB1 (14.3%) in CN-AML. Lastly, integrative genomic and transcriptomic analyses revealed GATA2 and SETBP1 ASE, including a novel non-coding SETBP1 mutation, potentially driving its high expression. Future studies are required to validate UBTF-TD lesions and refine the WT1 knockout, potentially revealing new resistance mechanisms amenable to treatment. LATS2 fusions also require validation to clarify their impact on the tumour-suppressive Hippo pathway. Finally, long-read and whole-genome sequencing may reveal additional mechanisms underlying GATA2 pathogenic expression, whereas functional assays of the novel non-coding SETBP1 variant may elucidate its role in driving AML. These findings may ultimately refine the prognosis and inform new therapeutic strategies for high-risk CN-AML.13 0Item Restricted Cardiometabolic Genomics and Pharmacogenomics in Filipino Americans: A Cross-Sectional Study(VIRGINIA COMMONWEALTH UNIVERSITY, 2024-12) Alrajeh, Khalifa Yousef; Price, Elvin; McClay, Joseph; Dixon, Dave; Diallo, Ana; Prom-Wormley, ElizabethHeart disease (HD) remains a leading cause of death in the country, with significant ethnic disparities. Filipino Americans (FAs), the third-largest Asian subgroup in U.S., face an elevated burden of dyslipidemia, a primary modifiable risk factor for HD. This community-based study addresses critical knowledge gaps by characterizing the cardiometabolic and genetic factors contributing to dyslipidemia among FAs and implications for personalized cardiovascular drug therapies, particularly statin pharmacogenomics (PGx). The first aim characterized the dyslipidemia prevalence in FAs and major ethnic subgroups using nationally representative NHANES data. FAs had the highest rates of elevated triglycerides. Particularly, middle-aged FA adults had the highest rates of elevated triglycerides, TC, and overall dyslipidemia compared to other ethnic groups. The lipid profiles of FA men was worse than FA women as well as men from other ethnic groups for all though FAs generally demonstrated higher HDL-C levels. Secondly, we examined associations between uric acid (UA) levels and lipid profiles, adjusting genetic and non-genetic factors. While elevated UA showed initial associations with adverse lipid profiles, these relationships largely diminished after adjustment, except for a threshold effect on TG at moderate UA levels. Furthermore, we identified significant associations between the APOE-e2 variant and lipid variations. Traditional risk factors including age, BMI, metabolic syndrome, and statin use emerged as strong predictors of lipid parameters. Thirdly, we characterized the allele frequencies of genetic variants with PGx relevance, including statin exposure/response. FA participants had the highest frequencies of decreased function ABCG2 among Europeans and African Americans, while the no function SLCO1B1*15 was common. Conversely, FAs had more normal function CYP2C9 variants with rare no function alleles. These distinct allele distributions indicate that FAs are more likely to require genotype-guided statins, based on their higher genetic risk for statin-related myopathy than other populations. This is the first application of the predesigned PGx (120-SNP) TaqMan® OpenArray® panel in FAs, though its design based on non-FAs may have limited detection of population-specific variants affecting statin response. This dissertation provides insights into cardiovascular health challenges in FAs and supports incorporating PGx data into clinical decision-making to optimize statin therapy. This work contributes to the broader mission of reducing health disparities by promoting PGx research in underrepresented populations and advancing personalized medicine approaches that account for ethnic diversity.19 0Item Restricted Regulatory and Social Acceptance Challenges in Using Artificial Intelligence in Genomic Diagnostics in Saudi Arabia: Applying the Responsive Regulation and Innovation Diffusion Model.(University College London (UCL), 2024-08-28) Alderaa, Khalid; Jong, SimchaThis study explores the regulatory and social acceptance challenges of integrating Artificial Intelligence (AI) into genomic diagnostics in Saudi Arabia, using the Responsive Regulation and Innovation Diffusion model as theoretical frameworks. Methodology: The research employs a narrative review methodology, emphasizing regulatory frameworks, public trust, and the cultural perceptions that influence the adoption of AI technologies. Findings: The study identifies that, although AI holds significant promise for advancing genomic diagnostics, its full integration is hindered by regulatory gaps and a low level of social acceptance. The research emphasises the importance of creating a flexible and dynamic regulatory framework that can evolve with AI advancements. It also highlights the crucial role of stakeholder engagement and public education in building trust and ensuring that innovation progresses without compromising public safety. Limitations: Key limitations of the study include the restricted scope of the literature review, which primarily focuses on the European Union and Saudi Arabia, and the fast-paced development of AI technology, which may limit the long-term applicability of the proposed models. Practical Implications: To improve the adoption of AI in healthcare, this study recommends the implementation of regulatory sandboxes, which would allow AI innovations to be tested in controlled environments. Additionally, fostering public trust through transparency and education is critical to ensuring the successful integration of AI technologies in genomic diagnostics.23 0