Polimorfizmi gena za glutation S-transferazu kao rani predskazatelj učinkovitosti metotreksata u liječenju juvenilnog idiopatskog artritisa

doctoral thesis

• Title (english): Glutathione S-transferase gene polymorphisms as an early predictor of methotrexate effectiveness in the treatment of juvenile idiopathic arthritis
• Author: Sanda Huljev Frković
• Mentor: Marija Jelušić (mentor)
• Committee member: Ivan Malčić (predsjednik povjerenstva)
• Committee member: Alenka Gagro (član povjerenstva)
• Committee member: Jadranka Sertić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2022-09-09, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pediatrics
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Cytology, Histology and Embryology
• Universal decimal classification (UDC): 616 - Pathology. Clinical medicine

Abstract

Uvod: Juvenilni idiopatski artritis (JIA) najčešća je reumatska bolest dječje dobi. Rana kontrola upalnog procesa u JIA korelira s povoljnijim ishodima liječenja. Odgovor na primjenu metotreksata (MTX), prvog lijeka druge linije liječenja djece s JIA je heterogen, s udjelom većim od 30 % djece u koje navedeni lijek nema učinka u smislu postizanja remisije. Kako je za procjenu učinka MTX nužan period od 3 do 6 mjeseci kontinuirane primjene, u djece u koje navedeni lijek neće djelovati gubi se mogućnost ranog postizanja remisije, odnosno smanjuje vjerojatnost povoljnog ishoda liječenja. Cilj rada bio je istražiti vrijednost određivanja delecijskih polimorfizama GSTM1 i GSTT1 kao predskazatelja učinkovitosti MTX u liječenju JIA. -----
Ispitanici i metode: U istraživanje je uključeno 109 JIA bolesnika: 46 bolesnika u kojih je tijekom terapije MTX postignuta stabilna klinička remisija u trajanju od minimalno 6 mjeseci i 63 bolesnika u kojih tijekom liječenja metotreksatom nije postignuta stabilna klinička remisija. U svih bolesnika uključenih u studiju određeni su delecijski polimorfizmi gena GSTM1 i GSTT1. -----
Rezultati: Između ispitivanih skupina JIA bolesnika nije nađeno statistički značajnih razlika u raspodjeli pojedinih delecijskih polimorfizama gena GSTM1 i GSTT1. Delecijski polimorfizam gena GSTM1 detektiran je u 40/63 (63,5 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 27/46 (58,7 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Delecijski polimorfizam gena GSTT1 detektiran je u 14/63 (22,2 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 8/46 (17,4 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Kombinacija delecijskih polimorfizama gena GSTM1 i GSTT1 detektirana je u 8/63 (12,7 %) ispitanika u kojih tijekom terapije MTX nije postignuta remisija te u 6/46 (13,0 %) ispitanika u kojih je tijekom terapije MTX postignuta remisija. Nije nađeno statistički značajnih razlika u raspodjeli pojedinih delecijskih polimorfizama niti njihove kombinacije između ispitivanih skupina.
Dodatno su analizirane razlike delecijskih polimorfizama gena GSTM1 i GSTT1 u skupini djece u koje tijekom liječenja MTX nije postignuta remisija, odnosno u koje je bilo potrebno liječenje bDMARD u odnosu na broj bDMARD potrebnih za postizanje remisije. U podskupini oboljele djece u kojoj je za postizanje remisije bila potrebna jedna ili više zamjena bDMARD u odnosu na podskupinu djece u kojoj je za postizanje remisije bio dostatan jedan bDMARD, statistički je značajno zastupljeniji nalaz pozitivnog genotipa polimorfizma gena GSTM1: 64,3 % naprema 28,6 %; P = 0,026. -----
Zaključak: Određivanje delecijskih polimorfizama gena GSTM1 i GSTT1 prema ovom istraživanju ne pomaže u detekciji djece oboljele od JIA u koje se neće postići remisija tijekom terapije MTX. No, statistički značajno češća pojavnost pozitivnog genotipa polimorfizma gena GSTM1 u podskupini oboljele djece u kojoj je za postizanje remisije bila potrebna jedna ili više zamjena bDMARD u odnosu na skupinu djece u koje je remisija postignuta jednim bDMARD, otvara nove horizonte u istraživanjima polimorfizama gena GSTs u sklopu JIA i drugih upalnih reumatskih bolesti.

Abstract (english)

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. Early control of the inflammatory process in JIA correlates with more favourable treatment outcomes. The effectiveness of the MTX, the first- line drug in JIA treatment is heterogeneous, with a proportion of more than 30% of children without effect in terms of achieving remission. Since an assessment of the MTX effects requires a period of 3–6 months of continuous administration, in more than 30% of children the possibility of early remission and favourable outcome of treatment is reduced. The aim of the research was to investigate the value of the determination of GSTM1 and GSTT1 genes deletion polymorphisms as the predictor of the MTX treatment effectiveness in JIA patients. -----
Subjects and methods: The study included 109 JIA patients: 46 patients who had achieved stable clinical remission for a minimum of 6 months during MTX therapy and 63 patients who did not achieve stable clinical remission during MTX therapy. In all patients enrolled in the study, the deletion polymorphisms of the GSTM1 and GSTT1 genes were determined. -----
Results: No statistically significant differences in the distribution of deletion polymorphisms were found between the JIA patient study groups. Deletion polymorphism of the GSTM1 gene was detected in 40/63 (63.5%) subjects who did not achieve remission during MTX therapy and 27/46 (58.7%) subjects who achieved remission during MTX therapy. Deletion polymorphism of the GSTT1 gene was detected in 14/63 (22.2%) subjects in whom remission was not achieved during MTX therapy and in 8/46 (17.4%) subjects in whom remission was achieved during MTX therapy. The combination of deletion polymorphisms for the GSTM1 and GSTT1 genes was detected in 8/63 (12.7%) subjects in whom remission was not achieved during MTX therapy and in 6/46 (13.0%) subjects in whom remission was achieved during MTX therapy. No statistically significant differences were found in the distribution of deletion polymorphisms or their combinations between the investigated groups.
The differences between the deletion polymorphisms of the GSTM1 and GSTT1 genes in the group of children in whom remission was not achieved during MTX therapy were further analyzed. In a subgroup of affected children in which one or more bDMARD changes were needed to achieve remission, positive genotype GSTM1 gene polymorphism was statistically significantly more frequently detected: 64.3% to 28.6%; P = 0.026. -----
Conclusion: According to this study, the determination of GSTM1 and GSTT1 gene deletion polymorphisms does not help in the distinction of JIA patients who will not achieve remission during MTX therapy. However, the statistically significantly more frequent occurrence of positive polymorphism of GSTM1 gene in a subgroup of children in which one or more changes of bDMARD were needed to achieve remission compared with the subgroup of children in whom remission was achieved by initial bDMARD, opens new horizons in GST gene polymorphism research in JIA and other inflammatory rheumatic diseases.

• Keywords: Artritis; juvenilni; Polimorfizam; genetski; Genotip; Ishod liječenja
• Keywords (english): Arthritis; Juvenile; Polymorphism; Genetic; Genotype; Treatment Outcome
• Language: croatian
• URN:NBN: urn:nbn:hr:105:811847
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 94 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-10-28 11:00:19