20.500.12556/RUL-187491 Povezanost polimorfizmov v genih IL12B, FCGR2A, FCGR3A, PTPN2, HLA-DRB9 in HLA-DQA1 z odzivom na zdravljenje ulceroznega kolitisa z golimumabom Association of polymorphisms in the IL12B, FCGR2A, FCGR3A, PTPN2, HLA-DRB9 in HLA-DQA1 genes with response to golimumab treatment of ulcerative colitis Ulcerozni kolitis je kronična vnetna črevesna bolezen, ki prizadene sluznico danke in debelega črevesja. Za zdravljenje zmerno hudih in hudih oblik bolezni se pogosto uporabljajo biološka zdravila iz skupine zaviralcev dejavnika tumorske nekroze alfa, med katera spada tudi golimumab. Kljub napredku je v klinični praksi pogosta primarna in sekundarna neodzivnost na zdravljenje, ki je lahko pogojena s farmakokinetičnimi in genetskimi dejavniki. Namen magistrske naloge je bil raziskati vpliv osmih izbranih polimorfizmov posameznega nukleotida v genih IL12B, FCGR2A, FCGR3A, PTPN2, HLA-DRB9 in HLA-DQA1 na terapevtski odziv pri bolnikih z ulceroznim kolitisom, zdravljenih z golimumabom. Genotipizacijo za 56 bolnikov smo izvedli z verižno reakcijo s polimerazo v realnem času z uporabo hidrolizirajočih sond. Genotipe smo statistično analizirali v povezavi z longitudinalnimi podatki o endoskopski oceni aktivnosti bolezni in o koncentracijah fekalnega kalprotektina kot biokemijskega kazalnika. Povezanost genotipov s trajanjem učinkovitosti zdravljenja smo vrednotili s Kaplan-Meierjevo analizo preživetja. Kot najmočnejši genetski napovedovalec neuspeha zdravljenja se je izkazal polimorfizem HLA-DQA1 rs2097432. Mutirani homozigoti CC so imeli značilno nižjo verjetnost za dosego endoskopske remisije v 14. tednu (OR = 0,17; p = 0,044), krajši čas do izgube odziva (p = 0,018) in 2,74-krat večje tveganje za izgubo odziva na terapijo (p = 0,0238) v primerjavi z nosilci vsaj enega alela T. Pri polimorfizmu FCGR2A rs1801274 smo ugotovili povezavo genotipa AA z boljšo biokemijsko remisijo v 6. (p = 0,0325) in 38. tednu (p = 0,0282). Polimorfizem IL12B rs6887695 je izkazal recesivni učinek na povišanje koncentracij fekalnega kalprotektina v 14. tednu, ki je postal statistično značilen šele ob prilagoditvi za spol. Pri polimorfizmu PTPN2 rs7234029 je mutiran alel A kazal trend k višjim vrednostim koncentracije fekalnega kalprotektina in slabšemu biokemijskemu odzivu, medtem ko pri ostalih polimorfizmih nismo potrdili vpliva na kazalnike odziva. Naša raziskava je prva, ki je potrdila vpliv polimorfizma HLA-DQA1 rs2097432 na odziv pri zdravljenju z golimumabom. Rezultati potrjujejo pomemben vpliv farmakogenetskih dejavnikov na odziv pri bolnikih z ulceroznim kolitisom. Ulcerative colitis is a chronic inflammatory bowel disease that affects the mucosa of the rectum and colon. Biological drugs from the group of tumor necrosis factor-alpha inhibitors, including golimumab, are frequently used to treat moderate-to-severe forms of the disease. However, primary and secondary treatment failure remain significant challenges and may be conditioned by pharmacokinetic and genetic factors. The aim of this master’s thesis was to investigate the influence of eight selected single nucleotide polymorphisms in the IL12B, FCGR2A, FCGR3A, PTPN2, HLA-DRB9 and HLA-DQA1 genes on the therapeutic response in patients with ulcerative colitis treated with golimumab. Genotyping of 56 patients was performed using real-time polymerase chain reaction with hydrolyzing probes. Genotypes were statistically analyzed in relation to longitudinal data on endoscopic disease activity scores and fecal calprotectin concentrations as a biochemical marker. The association between genotypes and the duration of treatment efficacy was evaluated using Kaplan-Meier survival analysis. The HLA-DQA1 rs2097432 polymorphism emerged as the strongest genetic predictor of treatment failure. Mutated CC homozygotes had a significantly lower probability of achieving endoscopic remission at week 14 (OR = 0.17; p = 0,044), a shorter time to loss of response (p = 0,018) and a 2.74-fold higher risk of loss of response to therapy (p = 0,0238) compared to carriers of at least one T allele. For the FCGR2A rs1801274 polymorphism, the AA genotype was associated with better biochemical remission at weeks 6 (p = 0,0325) and 38 (p = 0,0282). The IL12B rs6887695 polymorphism exhibited a recessive effect on the increase of fecal calprotectin concentrations at week 14, which became statistically significant only after adjustment for gender. Regarding the PTPN2 rs7234029 polymorphism, the mutated A alelle showed a trend toward higher fecal calprotectin concentrations and a poorer biochemical response, while no significant associations were confirmed for the remaining polymorphisms. To our knowledge, this is the first study to confirm the impact of the HLA-DQA1 rs2097432 polymorphism on the response to golimumab treatment. The results confirm the significant influence of pharmacogenetic factors on the response in patients with ulcerative colitis. ulcerozni kolitis golimumab farmakogenetika gen HLA-DQA1 gen FCGR2A ulcerative colitis golimumab pharmacogenetics gene HLA-DQA1 gene FCGR2A true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-09-11 08:45:08 2026-09-11 08:45:15 2026-09-13 03:28:03 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 2027-09-10 128688 32348.pdf 32348.pdf 1 130729D2F90458DF7B692AF8438E284D 2b58d6aad1704cda1d34e1ff54dd2fe08311394be947141b3f7ce9606560514a 52c0a702-adac-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=247127 Fakulteta za farmacijo 0 0 0