20.500.12556/RUL-182148 Pomen farmakogenetike pri zdravljenju ulceroznega kolitisa z ustekinumabom The role of pharmacogenetics in the treatment of ulcerative colitis with ustekinumab Ulcerozni kolitis je idiopatska kronična vnetna črevesna bolezen, katere pojavnost v razvitem svetu narašča, zato predstavlja pomemben zdravstveni izziv in pogosto področje raziskovanja. Med novejšimi možnosti terapije je biološko zdravilo ustekinumab, monoklonsko protitelo, ki zavira signalno pot interlevkinov 12 in 23 ter s tem zmanjšuje vnetni imunski odziv. V okviru farmakogenetskega pristopa smo v magistrski nalogi raziskali vpliv genetskih razlik na učinkovitost zdravljenja ulceroznega kolitisa z ustekinumabom. Študija je vključevala 34 bolnikov, pri katerih smo z metodo verižne reakcije s polimerazo v realnem času z uporabo hidrolizirajočih sond genotipizirali osem kandidatnih polimorfizmov v genih FCGR3A, FCGR2A, HLA-DRB9, HLA-DQA1, IL12B in PTPN2. Genetske podatke smo statistično analizirali v povezavi z longitudinalnimi kliničnimi podatki bolnikov o endoskopski oceni aktivnosti bolezni ter koncentraciji fekalnega kalprotektina kot biokemijskega kazalca črevesnega vnetja. Statistično značilne povezave smo zaznali pri treh polimorfizmih: rs6887695 (IL12B), rs1801274 (FCGR2A) in rs2395185 (HLA). Prisotnost variantnih alelov C pri rs6887695, G pri rs1801274 in T pri rs2395185 je bila povezana z večjo verjetnostjo doseganja endoskopskega odziva. V dominantnem modelu je bil v 24. tednu delež endoskopskega odziva višji pri nosilcih teh alelov v primerjavi z nenosilci (rs6887695: 86,7 % in 42,9 %; rs1801274: 77,3 % in 28,6 %; rs2395185: 85,7 % in 46,7 %), hkrati pa so imeli tudi nižje koncentracije fekalnega kalprotektina. Nadaljnja analiza je pokazala, da se verjetnost doseganja endoskopskega in biokemijskega odziva povečuje z naraščajočim številom zaščitnih alelov, kar potrjuje koncept aditivnega genetskega učinka. Bolniki s tremi ali več zaščitnimi aleli so imeli v 24. tednu približno 25-krat večje obete za doseganje endoskopskega odziva v primerjavi z bolniki brez zaščitnih alelov. Te ugotovitve predstavljajo osrednji rezultat naloge. Glavno omejitev raziskave predstavlja majhno število vključenih bolnikov in velika biološka variabilnost fekalnega kalprotektina. Kljub temu rezultati nakazujejo, da bi lahko genetske variacije v genih, ki sodelujejo pri regulaciji imunskega odziva, prispevale k razvoju bolj personaliziranega zdravljenja bolnikov z ulceroznim kolitisom. Ulcerative colitis is an idiopathic chronic inflammatory bowel disease with increasing incidence in developed countries, representing a significant healthcare challenge and an important field of research. Among newer therapeutic options is the biological drug ustekinumab, a monoclonal antibody that inhibits the interleukin-12/23 signaling pathway, thereby reducing the inflammatory immune response. In this thesis, we applied a pharmacogenetic approach to investigate the impact of genetic variability on the efficacy of ustekinumab treatment in patients with ulcerative colitis. The study included 34 patients, in whom eight candidate polymorphisms in the genes FCGR3A, FCGR2A, HLA-DRB9, HLA-DQA1, IL12B, and PTPN2 were genotyped using real-time polymerase chain reaction with hydrolysis probes. Genetic data were statistically analyzed in relation to longitudinal clinical data, including endoscopic disease activity and fecal calprotectin levels as a biochemical marker of intestinal inflammation. Statistically significant associations were observed for three polymorphisms: rs6887695 (IL12B), rs1801274 (FCGR2A), and rs2395185 (HLA). The presence of variant alleles C (rs6887695), G (rs1801274), and T (rs2395185) was associated with a higher likelihood of achieving an endoscopic response. In the dominant model, the proportion of patients achieving an endoscopic response at week 24 was higher among carriers of these alleles compared to non-carriers (rs6887695: 86.7% and 42.9%; rs1801274: 77.3% and 28.6%; rs2395185: 85.7% and 46.7%), and was also associated with lower fecal calprotectin levels. Further analysis demonstrated that the probability of achieving both endoscopic and biochemical response increased with the number of protective alleles, supporting the concept of an additive genetic effect. Patients carrying three or more protective alleles had approximately 25-fold higher odds of achieving an endoscopic response at week 24 compared to those without protective alleles. These findings represent the central result of this thesis. The main limitation of the study is the small number of included patients and the high biological variability of fecal calprotectin. Nevertheless, the results suggest that genetic variations in genes involved in immune regulation may contribute to the development of more personalized treatment strategies for patients with ulcerative colitis. ulcerozni kolitis ustekinumab farmakogenetika fekalni kalprotektin endoskopska ocena ulcerative colitis ustekinumab pharmacogenetics fecal calprotectin endoscopic assessment true false false [G. Pušnik] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-04-25 08:45:20 2026-04-25 08:45:29 2026-05-05 10:51:16 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 2027-04-24 616.34-002:575:615.37 125245 277034243 31963.pdf 31963.pdf 1 A856569D1BD3CB3080603E6DAC351E37 e0b650f4ba9bfa1d478fa7b2fe4399e51eec90d126c4145573a9e2dc19721a1e 1cce2d17-4072-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=233122 Fakulteta za farmacijo 0 0 0