Pharmacogenomics of thiopurines on Kosovo populationPasha, Flaka (Avtor) Mlinarič Raščan, Irena (Mentor) Krasniqi, Shaip (Komentor) thiopurinespharmacogenomicstherapeutic drug monitoringoverall survivaladverse outcomesThis dissertation evaluates the efficacy and safety of thiopurine treatment in patients with acute lymphoblastic leukemia (ALL), inflammatory bowel disease (IBD), and autoimmune disorders in Kosovo. Herein, we present identified and validated genetic polymorphisms affecting thiopurine metabolism, and correlations of thiopurine-related pharmacogenomic biomarkers with adverse treatment outcomes. We assessed the efficacy and safety of thiopurine treatment among children diagnosed with ALL in Kosovo (N=225), for the past 15-years. We documented 61% remission rate (95% CI: 54-67%), 11% relapse rate (95% CI: 7-16%), 20% mortality (95% CI: 13-26%), 55% 2-year event-free survival (EFS) (95% CI: 48-61%), 40% 5-year EFS (95% CI: 34-46%), 61% 2-year overall survival (OS) (95% CI: 55-68%), and 46% 5-year OS (95% CI: 40-53%). The survival rates were significantly lower compared to the existing literature. Furthermore, in the healthy population of Kosovo (N=299), we evaluated polymorphisms and variants influencing thiopurine metabolism. We observed the following minor allele frequencies (MAF): TPMT*2 - 0%, TPMT*3A - 2%, TPMT*3C - 0.1%, PACSIN2 rs2413739 - 48.8%, ITPA rs1127354 - 4%, MTHFR rs1801133 - 49.8%, and MTHFR rs1801131 - 27.4%. We identified five variants in NUDT15 gene, hence: rs45465203 - 13.5%, rs61973267 - 9%, rs79687000 - 2%, rs377238223 - 0.4%, and rs746071566 - 0.4%. MAFs for NUDT15 rs61973267, PACSIN2 rs2413739 and MTHFR rs1801133 were significantly higher compared to the global population (p<0.0001), while the MAF for ITPA rs1127354 was significantly lower than global and European population. Lastly, we evaluated the correlation between thiopurine-related pharmacogenomic biomarkers with biochemical and hematological parameters in 69 patients diagnosed with ALL, IBD and autoimmune disorders in Kosovo (13 ALL children; 56 adults with internal medicine disorders). We identified 11 patients with 6-TGN levels under thiopurine therapeutic range, 7 non-compliant patients, 2 non-responsive patients, 27 patients with 6-TGN levels >450 pmol/8×108 RBC, potentially under risk of myelotoxicity, and 6 patients with 6-MeMP levels >5700pmol/8×108 RBC under the risk of hepatotoxicity. We further carried out the correlation analyses of pharmacogenomic and biochemical biomarkers, indicating thiopurine-induced leukopenia and potential hepatotoxicity in a subset of patients. Results included in this dissertation set the foundation for establishing pharmacogenomic biomarkers and therapeutic drug monitoring services in Kosovo healthcare system, thus improving safety and efficacy of thiopurine-treated prospective patients through precision medicine.20252025-01-27 09:35:43Doktorsko delo/naloga166819sl