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Izpis gradiva Pomoč

Naslov:FARMAKOGENOMIKA IN VREDNOTENJE INTERMITENTNEGA ZDRAVLJENJA Z ANTAGONISTI LEVKOTRIENOV PRI OTROCIH S PERSISTENTNO ASTMO
Avtorji:ID Skerbinjek-Kavalar, Maja (Avtor)
ID Košnik, Mitja (Mentor) Več o mentorju... Novo okno
ID Potočnik, Uroš (Komentor)
ID Avčin, Tadej (Komentor)
ID Krajnc, Ivan (Član komisije za zagovor)
Datoteke:.pdf DR_Skerbinjek_Kavalar_Maja_2013.pdf (4,45 MB)
MD5: E9C87DD38C1706DF00C17EE7E4013C78
 
Jezik:Slovenski jezik
Vrsta gradiva:Doktorska disertacija
Organizacija:MF - Medicinska fakulteta
Opis:V naši raziskavi smo želeli preveriti, ali je pri otrocih in mladostnikih intermitentno zdravljenje blage astme z LTRA prav tako učinkovito kot kontinuirano zdravljenje z LTRA. UDK: 616.248-053.2:615.234:577.2(043.3) V kliničnem delu raziskave smo ugotavljali urejenost astme po letu dni zdravljenja z IGK, z LTRA kontinuirano in z LTRA intermitentno. Ugotoviti smo želeli vpliv različnih načinov zdravljenja na pljučno funkcijo, ACT-vprašalnik in na biomarkerje (pH in vnetne citokine, ki so značilni za astmatsko vnetje) v kondenzatu izdihanega zraka. V raziskavi o genetiki smo želeli določiti pogostnost nekaterih alelov in genotipov v kandidatnih genih pri astmatikih in zdravih kontrolah. Ovrednotiti smo želeli njihovo povezanost s tveganjem za razvoj astme in ugotoviti, ali so posamezni SNP-ji povezani z astmo kot tako ali le z značilnimi fenotipi astme. S farmakogenetsko analizo smo želeli ugotoviti, ali so določeni polimorfizmi genov, ki so bili v prejšnjih raziskavah povezani bodisi s tveganjem za razvoj astme bodisi z odzivom na zdravljenje astme, povezani z odgovorom otrok na zdravljene z IGK, z LTR kontinuirano in z LTR intermitentno. Hipoteze, da je učinkovitost zdravljenja blage astme z LTRA intermitentno glede na klinične pokazatelje enako učinkovita kot dolgotrajno protivnetno zdravljenjenje z IGK ali z LTRA kontinuirano, nismo potrdili. Kljub temu da so bili v skupini, zdravljeni z LTRA intermitentno, vključeni bolniki z blažjo astmo, je bilo potrebno pri nekaterih bolnikih uvesti kontinuirano protivnetno zdravljenje. Z raziskavo povezanosti genotipov s fenotipi astme smo potrdili pomen nekaterih alelov oziroma genotipov SNP-jev v kandidatnih genih za astmo pri slovenskih otrocih. ORMDL3 smo potrdili kot pomembni kandidatni gen za astmo. V naši raziskavi je povezan tako s tveganjem za razvoj astme kot tudi z neatopijsko astmo in z astmo brez rinitisa. Alel C v rs4795405 je povezan s tveganjem za razvoj astme pri slovenski populaciji otrok; lahko bi vplival na pojav neatopijskega fenotipa astme in astme brez rinitisa. Potrdili smo povezavo genotipa GG rs5744247 v IL18 s simptomi zgodnje alergije, ki poveča možnost za razvoj astme. Sicer ta SNP ni povezan z atopijsko astmo, se pa je statistično značilno pogosteje pojavljal pri otrocih z astmo, ki imajo zgodnje simptome alergije, pogostnost genotipa GG pri otrocih brez zgodnjih simptomov alergije pa je bila podobna pogostnosti pri zdravih otrocih. Povezave TBXA2R z atopijsko astmo pri slovenskih otrocih nismo potrdili, našli pa smo povezavo med rs3786989 za TBXA2R in pojavom zgodnjih simptomov alergije ter povezavo med rs8113232 in astmo, ki ji je pridružen rinitis. Prav tako nismo potrdili povezave med rs833058 za VEGF in atopijsko astmo, temveč smo ugotovili, da je ta SNP povezan s pojavom zgodnjih simptomov alergije pri astmatikih, povezave med SNP rs2146323 v VEGFA in astmo ali posameznimi fenotipi nismo potrdili. SNP rs7025417 za gen IL-13 in SNP rs324011 za STAT6 nista bila povezana s tveganjem za razvoj astme ali s katerim od preučevanih fenotipov astme. SNP-ji rs3786989 in rs8113232 v TBXA2R, rs4795405 v ORMDL3 ter rs833058 v VEGFA so bili povezani s stopnjo izražanja astme, iste SNP-je smo povezali tudi bodisi s tveganjem za razvoj astme bodisi s posameznimi fenotipi astme, kar kaže na njihovo vlogo v patogenezi te bolezni. Rezultati vpliva genotipa na odziv na protivnetno zdravljenje z IGK kažejo vpliv polimorfizma rs1295686 za gen IL-13, saj imajo homozigoti za alel A boljši odgovor na zdravljenje, vpliv polimorfizma rs2139142 za gen MAPK3, kjer imajo homozigoti za alel G boljši odgovor na zdravljenje, vsi glede na porast FEV1. Boljšo urejenost astme glede izboljšanja % ACT-vprašalnika pa smo zabeležili pri polimorfizmu rs13298282 za gen TLE4 pri nosilcih vsaj enega alela C. Pri kontinuiranem zdravljenju z LTRA smo zabeležili porast pljučne funkcije oziroma FEV1 za polimorfizem rs1295686 za gen IL-13 za bolnike z vsaj enim alelom A, za polimorfizem rs2244012 za gen RAD50 pri homozigotih za alel C in z
Ključne besede:Astma, otrok, zdravljenje, genetika
Kraj izida:Maribor
Leto izida:2013
PID:20.500.12556/DKUM-42858 Novo okno
COBISS.SI-ID:269840128 Novo okno
NUK URN:URN:SI:UM:DK:TMXFUQZZ
Datum objave v DKUM:13.11.2013
Število ogledov:3046
Število prenosov:320
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
Področja:MF
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:PHARMACOGENOMICS AND EVALUATION OF TREATMENT WITH INTERMITTENT LEUKOTRIENES IN CHILDREN WITH ASTHMA
Opis:The purpose of this research was to establish whether intermittent treatment of mild asthma with LTRA in children and adolescents is as effective as continuous treatment with LTRA. In the clinical part of the research, we established the regulation of asthma in children after one-year treatment with intermittent glucocorticoids (IGC) as a positive control, continuous LTRA and intermittent LTRA. We aimed to establish the influence of various modes of treatment on biomarkers (pH and inflammatory cytokines characteristic of asthmatic inflammation) in the exhaled breath condensate. In the genetic part of the research, we aimed to determine the prevalence of some alleles and genotypes in candidate genes in asthmatics and healthy controls, to evaluate their association with the risk of developing asthma, and to assess whether specific SNPs are associated with asthma in general, or only with distinctive asthma phenotypes. Using pharmacogenetic analysis, we aimed to establish whether specific genetic polymorphisms, which, in previous research, were associated with either the risk of developing asthma or the asthma treatment response, are associated with the children’s response to treatment with IGC, continuous LTR and intermittent LTR. We were unable to confirm the hypothesis that the efficacy of treating mild asthma with intermittent LTRA, with regard to clinical parameters, is not less effective than long-term anti-inflammatory treatment with IGC or continuous LTRA. Despite the fact that patients with mild asthma were included in the group treated with intermittent LTRA, it was necessary to instigate regular treatment with inhaled glucocorticoids in a significant proportion of patients. With our research into the association of genotypes with asthma phenotypes, we confirmed the significance of some alleles or genotypes of SNPs in the asthma candidate genes in Slovenian children. ORMDL3 was confirmed as an important candidate gene for asthma. In our research it was associated with the risk of developing asthma, non-atopic asthma and asthma without rhinitis. Allele C in rs4795405 is associated with the risk of developing asthma in the Slovenian child population, which could influence the appearance of the non-atopic phenotype of asthma and asthma without rhinitis. We confirmed the association of the GG rs5744247 genotype in IL18 with early allergy, which increases the chance of developing asthma. Although this SNP is not associated with atopic asthma, it is statistically more frequently found in children with asthma who have early symptoms of allergy. The prevalence of the GG genotype in children without early symptoms of allergy was similar to that in healthy children. The association of TBXA2R with atopic asthma in Slovenian children was not confirmed, but we found an association between rs3786989 in TBXA2R and the appearance of early symptoms of allergy and between rs8113232 and asthma that is associated with rhinitis. Similarly, we were unable to confirm an association between rs833058 in VEGF and atopic asthma, but we established that this SNP is associated with the appearance of early symptoms of allergy in asthmatics. No association was found between the SNP rs2146323 in VEGFA and asthma or particular phenotypes. SNP rs7025417 in IL-13 gene and the SNP rs324011 in STAT6 gene were not associated with the risk of developing asthma or with any of the studied asthma phenotypes. SNPs were also analyzed in relation to the degree of asthma expression, with rs3786989 and rs8113232 in TBXA2R, rs4795405 in ORMDL3 and rs833058 in VEGFA being associated with the degree of asthma expression. The same SNPs were also found to be associated either with the risk of developing asthma or with particular asthma phenotypes, which suggests their role in the pathogenesis of this disease. Results of the influence of genotype on the response to anti-inflammatory treatment with IGC show the influence of the polymorphism rs1295686 in IL-13 gene, since homozygotes for the A allele have a better response to treatment, and the influence o
Ključne besede:Asthma, child, treatment, genetics


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