Povezava polimorfizmov in izražanja izbranih genov z odzivom na zdravljenje bolnikov s Crohnovo boleznijo z adalimumabom

Gabor, Urška

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Title:	Povezava polimorfizmov in izražanja izbranih genov z odzivom na zdravljenje bolnikov s Crohnovo boleznijo z adalimumabom
Authors:	ID Gabor, Urška (Author) ID Potočnik, Uroš (Mentor) More about this mentor... ID Skok, Pavel (Comentor)
Files:	MAG_Gabor_Urska_2014.pdf (2,29 MB) MD5: 2EE7F3AC7DAB4E00951DB1C89861BDEB
Language:	Slovenian
Work type:	Master's thesis/paper
Typology:	2.09 - Master's Thesis
Organization:	FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:	Crohnova bolezen (CB) je avtoimunska motnja neznane etiologije. Trenutno največ potenciala za uspešno obvladovanje bolezni izkazujejo biološka zdravila, med katera spada tudi adalimumab (ADA). Klinične raziskave so pokazale, da je ADA varno in učinkovito zdravilo. Farmakogenetske raziskave pa so za ADA še v začetni stopnji. Namen magistrskega dela je bil ugotoviti ali obstaja povezava med odzivom na zdravljenje z ADA in izbranimi polimorfizmi posameznega nukleotida (ang.: SNP za »Single Nucleotide Polymorphism«) oziroma izražanjem izbranih genov pri slovenskih bolnikih s CB. Izbrali smo polimorfizme in gene, ki so v predhodnih študijah pokazali močno povezavo s CB, so vključeni v metabolizem zdravil, so povezani z imunskim odzivom in vnetjem ali s sorodnimi kompleksnimi boleznimi. Genotipe za izbrane polimorfizme smo pridobili iz rezultatov genotipizacije z uporabo mikromreže »Immunochip«. Izražanje genov smo merili v 0., 4., 12. 20. in 30. tednu od začetka zdravljenja z verižno reakcijo s polimerazo v realnem času (ang.: »Real-time PCR«). Pri primerjavi demografskih podatkov bolnikov smo ugotovili, da je med dobrimi odzivniki signifikantno manjši odstotek kadilcev v primerjavi s slabimi odzivniki (p = 0,042). Pri asociacijski analizi pri izključno CB bolnikih, zdravljenimi z ADA, smo za SNP rs2395185 (gen HLA-DQA1) ugotovili, da je frekvenca alela G (67,5%) in genotipa G/G (44,2%) signifikantno nižja pri bolnikih v primerjavi s kontrolami (77,6% in 60,6%, p = 0,023 in p = 0,011). Predpostavljamo, da alel G (oziroma genotip G/G) zmanjšuje tveganje za bolezen. Pri SNP-jih rs10919563 (gen PTPRC) in rs2241880 (gen ATG16L1) smo ugotovili, da imajo dobri odzivniki statistično nižjo frekvenco genotipa G/G v 30. tednu (p = 0,045 za rs10919563 in p = 0,025 za rs2241880) v primerjavi s slabimi odzivniki. Z Mann-Whitneyevim neparametričnim testom smo primerjali izražanje genov pred ter po tednih zdravljenja. Opazili smo, da je pri genih SLC22A4, PSMD3, AHSA2, RPRD2 in PUS10 bilo izražanje med dobrimi in slabimi odzivniki spremenjeno že pred začetkom zdravljenja. Pri treh genih (ATG16L1, RPRD2 in PUS10) je bilo izražanje glede na 0. teden signifikantno spremenjeno čez celoten potek opazovanega zdravljenja. Najbolj statistično signifikantne rezultate smo dobili za gen ATG16L1, kjer je bila p-vrednost znašala od 1,0×10-6 do 2,2×10-18. Pri primerjavi izražanja genov med dobrimi in slabimi odzivniki glede na indeks ∆IBDQ, smo ugotovili statistično signifikantne razlike med skupinama za gen ATG16L1 in gen SLC22A5. V raziskavi smo ugotovili, da so določeni preiskovani polimorfizmi in geni povezani z odzivom na ADA, potrebne pa so še nadaljnje raziskave, da bi se dokazala njihova vloga farmakogenomskih označevalcev.
Keywords:	Crohnova bolezen, polimorfizem posameznega nukleotida, izražanje genov, farmakogenomika, biološka zdravila, adalimumab
Place of publishing:	Maribor
Publisher:	[U. Gabor]
Year of publishing:	2014
PID:	20.500.12556/DKUM-45615
UDC:	575.16(043.2)
COBISS.SI-ID:	5100607
NUK URN:	URN:SI:UM:DK:Y6IWSBOJ
Publication date in DKUM:	11.09.2014
Views:	3100
Downloads:	339
Metadata:
Categories:	KTFMB - FKKT
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Secondary language

Language:	English
Title:	Association of polymorphisms and expression of selected genes with response to treatment of Crohn's disease patients with adalimumab
Abstract:	Crohn's disease (CD) is an autoimmune disorder of unknown etiology. Currently, the greatest potential for successful management of the disease is exhibited by biological therapeutics, including adalimumab (ADA). Clinical trials have shown that ADA is a safe and effective medicine. Pharmacogenetic studies concerning ADA, however, are still in an early stage. The purpose of this master thesis was to determine whether there is a correlation between response to treatment with ADA and selected single nucleotide polymorphisms (SNPs) and the expression of selected genes in Slovenian patients with CD. We selected polymorphisms and genes, which have shown a strong association with CD in previous studies, genes that are involved in drug metabolism, associated with immune response and inflammation or with related complex diseases. Genotypes for selected polymorphisms were obtained from the results of genotyping using the "Immunochip" microarray. Gene expression was measured at weeks 0, 4, 12, 20 and 30 weeks after initiation of treatment using Real-time polymerase chain reaction (PCR). When comparing the demographic data of patients we have found that there is a significantly lower percentage of smokers amongst patients with good response compared with patients with poor response (p = 0.042). Association analysis in exclusively ADA treated CD patients showed the frequency of the G allele (67,5%) and genotype G / G (44,2%) for the SNP rs2395185, HLA-DQA1 gene, was significantly lower in patients compared to controls 77,6% in 60,6%, p = 0,023 in p = 0,011). We presume that G allele (or G/G genotype) reduces the risk of disease. For SNPs rs10919563 (gen PTPRC) and rs2241880 (ATG16L1 gene) we have found that good responders have statistically lower frequency of G/G genotype in week 30 (p = 0.045 for rs10919563 and p = 0.025 for rs2241880) compared to poor responders. The Mann-Whitney nonparametric test was used for comparison of gene expression prior to and throughout the treatment. We have determined a difference in expression of genes SLC22A4, PSMD3, AHSA2, RPRD2 in PUS10 prior to the treatment. In three genes (ATG16L1, RPRD2 and PUS10) expression was significantly changed relatively to week 0 throughout the treatment. The most statistically significant results were obtained for gene ATG16L1, with a p-value ranging from 1.0 × 10-6 to 2.2 × 10-18. When comparing gene expression between good and poor responders according to the index ΔIBDQ, we found statistically significant differences between the groups for ATG16L1 gene and SLC22A5 gene. In this study, we have determined that some of the investigated polymorphisms and genes are associated with the response to ADA. However, further researchis needed to prove their role of pharmacogenomic markers.
Keywords:	Crohn's disease, single nucleotide polymorphism, gene expression, pharmacogenomics, biological drugs, adalimumab

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