Big Data Genomic Approaches for Understanding Nicotine Metabolism and Associated Phenotypes
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| Vydáno v: | ProQuest Dissertations and Theses (2025) |
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ProQuest Dissertations & Theses
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| On-line přístup: | Citation/Abstract Full Text - PDF |
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| 045 | 2 | |b d20250101 |b d20251231 | |
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| 100 | 1 | |a Giratallah, Haidy | |
| 245 | 1 | |a Big Data Genomic Approaches for Understanding Nicotine Metabolism and Associated Phenotypes | |
| 260 | |b ProQuest Dissertations & Theses |c 2025 | ||
| 513 | |a Dissertation/Thesis | ||
| 520 | 3 | |a CYP2A6, a genetically variable enzyme, is crucial in nicotine metabolism, affecting smoking behaviours and health outcomes. CYP2A6 activity can be measured phenotypically (i.e., the nicotine metabolite ratio, NMR) or genomically (i.e., a weighted genetic risk score, wGRS). The first aim was to identify the optimal urinary NMR by comparing them to plasma NMR and nicotine clearance; 768 plasma and urine samples were analyzed using Pearson correlations, regression analyses, and ANOVAs. The findings revealed that NMRT/F (total trans-3’-hydroxycotinine/free cotinine) was the most optimal urinary alternative to plasma NMR for measuring CYP2A6 activity, followed by NMRF/F (free trans-3’-hydroxycotinine/free cotinine). NMRT/T (total trans-3’-hydroxycotinine/total cotinine) had the least utility as it is influenced substantially by variation in cotinine glucuronidation. The second aim was to utilize a wGRS for CYP2A6 activity (e.g., NMR) to identify associations with disease risk and age of diagnosis. A phenome-wide association study of 395,887 United Kingdom Biobank participants was conducted, followed by Mendelian Randomization and survival analyses. Six respiratory disease-related signals were identified, showing that faster CYP2A6 activity increased chronic obstructive pulmonary disease (COPD) and lung cancer (LC) risk and led to higher risk for younger diagnosis age in current smokers. The third aim was to examine whether smoking quantity mediated the CYP2A6 activity effect on COPD and LC. Two-step mediated Mendelian Randomization and mediation analyses were conducted using three smoking quantity measures and their genetic instruments. Smoking quantity fully mediated COPD risk but only partially mediated LC risk, suggesting other mechanisms contribute to CYP2A6’s impact on LC beyond smoking quantity. The final aim was to refine the wGRS by incorporating putatively causal genetic variants identified in African ancestry to improve its portability across populations. Variants identified through Bayesian fine-mapping in 953 African ancestry participants were incorporated into the wGRS, with its portability assessed in 933 European ancestry participants. These variants improved the portability from African to European ancestry by ~40%, explaining 5.4% more variation in CYP2A6 activity. These findings enhance, utilizing the latest big-data genomics approaches, the field's understanding of CYP2A6's role in nicotine metabolism, smoking-related disease risk, and potential genetic factors influencing smoking behaviours and disease risk. | |
| 653 | |a Pharmacology | ||
| 653 | |a Epidemiology | ||
| 653 | |a Genetics | ||
| 653 | |a Oncology | ||
| 773 | 0 | |t ProQuest Dissertations and Theses |g (2025) | |
| 786 | 0 | |d ProQuest |t ProQuest Dissertations & Theses Global | |
| 856 | 4 | 1 | |3 Citation/Abstract |u https://www.proquest.com/docview/3234825835/abstract/embedded/7BTGNMKEMPT1V9Z2?source=fedsrch |
| 856 | 4 | 0 | |3 Full Text - PDF |u https://www.proquest.com/docview/3234825835/fulltextPDF/embedded/7BTGNMKEMPT1V9Z2?source=fedsrch |