20.500.12556/RUL-187108 Povezava polimorfizmov izbranih genov s potekom bolezni pri bolnikih z aksialnim spondiloartritisom, zdravljenih s tarčno terapijo Association of polymorphisms in selected genes with disease course in patients with axial spondyloarthritis treated with targeted therapy Ankilozirajoči spondilitis (AS) je kronična vnetna bolezen. Mehanizem nastanka je entezitis, kostenenje in ankiloza sklepa. Prizadene predvsem hrbtenico in sakroiliakalna sklepa. Bolnik ima izrazito slabšo kakovost življenja, zato je cilj hitrejša postavitev diagnoze in izbira pravega zdravljenja. Dandanes za AS ne poznamo zanesljivega biološkega označevalca. Uporabljamo HLA-B27, ki ima omejeno diagnostično občutljivost in specifičnost, kar poveča težnjo po iskanju novih bioloških označevalcev, raziskujejo predvsem vpliv različnih genov, ki bi lahko pomagali pri diagnozi. Namen magistrske naloge je bil preveriti pojavnost na osnovi literature izbranih polimorfizmov v slovenski skupini bolnikov z AS, vpisanih v register, ki ga vodi Klinični oddelek za revmatologijo UKC Ljubljana. Izbrali smo: ERAP1 (rs26653, rs2287987, rs30187, rs27044, rs26618, rs2032890, rs27434), ERAP2 (rs2549782), TNF (rs361525, rs1800629, rs1799724), TNFRSF1A (rs767455), TNFRSF1B (rs1061622) in MICA (rs1051792). Iz vzorcev polne venske krvi 106 bolnikov smo izolirali DNA, preverili koncentracijo DNA ter izvedli genotipizacijo z uporabo PCR in hidrolizirajočih sond TaqMan. Po pregledu podatkov iz registra in izločitvi 4 bolnikov zaradi spremenjene diagnoze ali zdravljenja z drugo skupino zdravil smo pri analizi upoštevali podatke 93 bolnikov. Po preverjanju Hardy-Weinbergovega ravnovesja smo ocenili njihovo reprezentativnost ter kakovost genotipizacije. Izračunali smo frekvence mutiranih alelov za 14 izbranih polimorfizmov in jih primerjali s podatki iz literature za zdravo evropsko populacijo. Pri genih ERAP1, ERAP2, TNF, TNFRSF1A, TNFRSF1B, MICA smo osmim polimorfizmom določili višjo pojavnost mutiranih alelov. Ti so verjetno povezani z večjim tveganjem za razvoj bolezni. Najizraziteje sta izstopala dva polimorfizma rs1799724 (gen TNF) in rs1051792 (gen MICA), kar nakazuje na močnejšo povezanost s tveganjem za razvoj bolezni. Šestim polimorfizmom smo določili nižje frekvence, kar lahko nakazuje na potencialno zaščitno vlogo. Ovrednotili smo povezavo genotipov s fenotipskimi značilnostmi bolezni. Obliko bolezni (aksialna ali aksialna in periferna) smo povezali z genom MICA, težko obvladljivo bolezen in pojav uveitisa pa z genom TNFRSF1A. Rezultati nakazujejo na potencialno vlogo obeh genov pri oblikovanju klinične slike AS ter predstavljajo podlago za nadaljnje raziskave. Ankylosing spondylitis is a chronic inflammatory disease driven by enthesitis, progressive ossification and eventual ankylosis of affected joints, most prominently the spine and sacroiliac joints, which substantially reduces patients’ quality of life and highlights the need for early diagnosis and appropriate therapeutic decision making. A reliable biological marker for the disease is still lacking; although HLA B27 is routinely used, its limited diagnostic sensitivity and specificity motivate ongoing efforts to identify new biomarkers, particularly genetic ones. The aim of the master’s thesis was therefore to investigate, based on published literature, the prevalence of selected polymorphisms in a Slovenian cohort of patients with ankylosing spondylitis enrolled in the registry of the Department of Rheumatology at the University Medical Centre Ljubljana. DNA was isolated from whole venous blood samples of 106 patients, its concentration was assessed, and genotyping was performed using PCR and hydrolysis (TaqMan) probes. After reviewing registry data and excluding four patients due to revised diagnoses or treatment with a different drug class, 93 patients were included in the final analysis. Hardy–Weinberg equilibrium was evaluated to confirm sample representativeness and genotyping quality, and mutant allele frequencies for fourteen selected polymorphisms were calculated and compared with published data for the healthy European population. Across the genes ERAP1, ERAP2, TNF, TNFRSF1A, TNFRSF1B and MICA, eight polymorphisms showed higher mutant allele frequencies, suggesting a potential association with increased susceptibility to ankylosing spondylitis, with rs1799724 in the TNF gene and rs1051792 in the MICA gene standing out most clearly as markers of elevated risk. Six polymorphisms exhibited lower mutant allele frequencies, which may indicate a protective role. Genotype–phenotype analyses further revealed that the clinical form of the disease, whether purely axial or axial with peripheral involvement, was associated with variation in the MICA gene, while difficult to control disease and the occurrence of uveitis were linked to TNFRSF1A. These findings suggest that both genes may influence the clinical presentation of ankylosing spondylitis and provide a foundation for future research aimed at improving diagnostic precision and understanding disease mechanisms. ankilozirajoči spondilitis frekvenca alelov genetski dejavniki HLA-B27 tveganje za razvoj ankylosing spondylitis allele frequencies genetic factors HLA B27 disease risk true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-09-09 08:45:04 2026-09-09 08:45:09 2026-09-10 04:30:46 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 128495 33793.pdf 33793.pdf 1 8B69E5BF41ED0D761AE8A55A67579CB8 feb060899026b1566580890d925ec7a760be2136b48bdc554ebbb2b94b301cab fd4d97d3-ac19-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=246552 Fakulteta za farmacijo 0 0 0