magistrsko delo
Alja Čontala (Avtor), Uroš Potočnik (Mentor), Pavel Skok (Komentor)

Povzetek

Faktor tumorske nekroze alfa (TNFα) je glavni provnetni citokin, ki je vključen v imunski odgovor pri Crohnovi bolezni (CB). Za zdravljenje CB se v primerih, ko standardna terapija s kortikosteroidi in antibiotiki ni uspešna, uporabljajo zdravila, ki delujejo proti citokinu TNFα (antiTNF), kot sta infliksimab (IFX) in adalimumab (ADA), vendar pa se približno tretjina bolnikov na takšno terapijo ne odziva. Cilj magistrskega dela je bil ugotoviti, ali izražanje genov TNFAIP6, S100A8, IL11, G0S2 in S100A9 v krvnih limfocitih in črevesni sluznici slovenskih bolnikov s CB vpliva na odziv na terapijo z ADA in ali je možno z izbranimi geni napovedati odziv na zdravljenje, kar bi lahko bil korak naprej k personaliziranemu zdravljenju CB. Izražanje izbranih genov smo izmerili z verižno reakcijo s polimerazo v realnem času (rt-PCR) pred terapijo in v 4., 12., 20. in 30. tednu terapije. Genotipe za izbrane polimorfizme smo pridobili iz mikromreže »Immunochip«. Odziv na terapijo smo ocenili s pomočjo IBDQ vprašalnika in nivoja CRP v krvi. Za statistično obdelavo smo uporabili statistični paket SPSS. Ugotovili smo signifikantno spremenjeno izražanje gena S100A8 pri primerjavi izražanja gena pred terapijo z izražanjem v 4. (p = 5×10-5, Z = -3,975) in 12. tednu (p=0,050). Signifikantno povišano ekspresijo gena S100A9 smo ugotovili po štirih tednih zdravljenja (p = 0,012). Pri primerjavi izražanja genov pred terapijo in v posameznih tednih med terapijo pri istem bolniku smo ugotovili dve signifikantni povezavi v okviru 95 % intervala zaupanja. Za gen S100A8 smo po 4 tednih terapije ugotovili signifikantno višje izražanje tega gena, saj je razlika median 2-ddct znašala 0,519 (p = 0,009), po 20. tednih zdravljenja z ADA pa smo ugotovili signifikantno nižje izražanje gena S100A9 (p = 0,045). Na podlagi IBDQ vprašalnika in izmerjene ekspresije izbranih genov smo ugotovili povečano ekspresijo gena G0S2 po 30. tednih zdravljenja z ADA (p = < 1×10-8, Z = -5,745), signifikantno nižje pa je bilo tudi izražanje gena TNFAIP6 pri dobrih odzivnikih na terapijo po 20. tednih terapije. Glede na kriterij CRP smo ugotovili signifikantno višjo ekspresijo gena G0S2 po 20. tednih terapije z ADA pri dobrih odzivnikih (p = 0,022). Ugotovili smo, da so proučevani geni in SNP-ji povezani z odzivom na ADA pri bolnikih s CB in nedvoumno predstavljajo dobre kandidate za potencialne napovedovalce odziva na zdravljenje CB z ADA. V prihodnosti je potrebno identificirati še večje število genov za napoved odziva in jih združiti v ustrezen napovedni model.

Ključne besede

Crohnova bolezen;adalimumab;antiTNF;genska ekspresija;napoved odziva;biološka zdravila;magistrske naloge;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UM FKKT - Fakulteta za kemijo in kemijsko tehnologijo
Založnik: [A. Gabor]
UDK: 612.336(043.2)
COBISS: 20298262 Povezava se bo odprla v novem oknu
Št. ogledov: 1497
Št. prenosov: 129
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: EXPRESSION OF GENES TNFAIP6, S100A8, IL11, G0S2 AND S100A9 IN BLOOD LYMPHOCYTES AND INTESTINAL MUCOSA OF CROHN'S DISEASE PATIENTS AS A PREDICTIVE BIOMARKER FOR RESPONSE TO TREATMENT WITH ADALIMUMAB
Sekundarni povzetek: Tumor necrosis factor alpha (TNFα) is a major pro-inflammatory cytokine that is involved in the immune response in Crohn's disease (CD). In patients that do not respond to standard therapy with corticosteroids and antibiotics for treatment of CD, are used medicines that act against the cytokine TNF (antiTNF) such as infliximab (IFX) and adalimumab (ADA). The problem is that about one third of patients do not respond to such therapy. The aim of the master thesis was to determine whether gene expression of TNFAIP6, S100A8, IL11, G0S2 and S100A9 in blood lymphocytes and intestinal mucosa in Slovenian patients with CD affect the response to treatment with ADA and whether it is possible to predict the response to treatment with the selected genes. It could be a step towards personalized treatment of CD. The expression of selected genes was measured by polymerase chain reaction in real-time (rt-PCR) before therapy and at 4, 12, 20 and 30 weeks of therapy. Genotypes for selected polymorphisms were obtained from microarrays "Immunochip." Response to therapy was assessed by questionnaire IBDQ and CRP levels in the blood. The SPSS statistical package was used for statistical analysis. We found significantly altered gene expression of S100A8 gene expression when compared to prior therapy with expression at week 4 (p = 5 × 10-5, Z = -3.975) and week 12 (p = 0.050). Significantly higher expression of S100A9 gene was found after 4 weeks of treatment (p = 0.012). When comparing the gene expression prior the therapy and in weeks during therapy in the same patient, we found 2 significant associations within the 95% confidence interval. For gene S100A8 after 4 weeks of therapy, there was a significant higher expression of this gene, as the difference of medians 2-ddct was 0.519 (p = 0.009) and after 20 weeks of treatment with the ADA, we found a significantly lower gene expression of S100A9 (p = 0.045). Based on IBDQ questionnaire and measured gene expression, we found an increased expression of the gene G0S2 after 30 weeks of treatment with ADA (p = <1 × 10-8, Z = -5.745) significantly lower, it was also the expression of a gene TNFAIP6 in good responders to treatment after 20 weeks of therapy. According to the CRP criteria, we found a significantly higher expression of the gene G0S2 after 20 weeks of therapy with ADA in good responders (p = 0.022). We have found that studied genes and SNPs are associated with responding to treatment with ADA in patients with CD and unambiguously represent good candidates for potential predictors of response to treatment of CD with ADA. In the future it is necessary to identify greater number of genes to predict response and combine them into the appropriate predictive model.
Sekundarne ključne besede: Crohn's disease;adalimumab;antiTNF;gene expression;biological drugs;response prediction;
URN: URN:SI:UM:
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Strani: X, 79 str.
ID: 9161534