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The functional analysis of the C20068T gene variant in the 3' end of the prothrombin gene and its role in the pathogenesis of thrombophilia

dc.contributor.advisorĐorđević, Valentina
dc.contributor.otherSavić-Pavićević, Dušanka
dc.contributor.otherRadojković, Dragica
dc.contributor.otherKovač, Mirjana
dc.contributor.otherTomić, Branko
dc.creatorPruner, Iva B.
dc.date.accessioned2016-07-10T17:07:28Z
dc.date.available2016-07-10T17:07:28Z
dc.date.available2020-07-03T08:13:29Z
dc.date.issued2014-06-10
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/5674
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=3107
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:11393/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024770226
dc.description.abstractProtrombin (Faktor II) je prekursor trombina, jednog od ključnih molekula u održavanju hemostazne ravnoteže. Povišeni nivo protrombina dovodi do poremećaja hemostazne ravnoteže i stanja hiperkoagulacije, koje se manifestuje pojavom tromboza. Pokazano je da 3kraj protrombinskog gena poseduje nekanonsku organizaciju, usled čega je podložan mutacijama koje dovode do povećane ekspresije protrombina i povišenog rizika za pojavu trombofilije. U okviru prethodne studije, sprovedene u Laboratoriji za molekularnu biologiju, Instituta za molekularnu genetiku i genetičko inženjerstvo, Univerziteta u Beogradu, u poslednjem egzonu gena za protrombin identifikovana je promena citozina (C) u timin (T) na mestu 20068. Ova genska varijanta dovodi do zamene CGC kodona za arginin u CGT kodon koji takođe kodira za arginin na poziciji 608 u proteinu. U bazi dsSNP/NCBI je klasifikovana kao sinonimna promena, pod brojem rs3136532. Pokazano je da je ova genska varijanta zastupljenija kod pacijenata sa trombozama i da njeno prisustvo dovodi do povećane ekspresije iRNK. Prvi deo istraživanja, u okviru ove doktorske disertacije, podrazumevao je određivanje učestalosti genske varijante C20068T u grupi pacijenata sa trombofilijom, kao i u odgovarajućoj grupi zdravih ispitanika, čime bi se utvrdilo da li ova varijanta predstavlja potencijalni novi trombofilni marker. Drugi deo istraživanja obuhvatio je funkcionalnu analizu C20068T varijante, u cilju rasvetljavanja mehanizma kojim ova sinonimna varijanta utiče na promenu ekspresije gena za protrombin. U okviru ove studije testirano je ukupno 797 ispitanika, od toga 606 pacijenata i 191 ispitanik kontrolne grupe. Pacijenti su podeljeni u grupe, shodno poremećaju od koga su bolovali, u grupu pacijenata sa trombotičkim poremećajima (443 pacijenta, od čega: 106 sa cerebrovaskularnim insultom, 101 sa plućnim embolizmom, 175 sa trombozom dubokih vena i 61 sa kombinovanim trombotičkim poremećajima) i grupu pacijentkinja sa spontanim pobačajima (163 pacijentkinje). U grupi pacijenata sa cerebrovaskularnim insultom detektovana su tri heterozigotna nosioca C20068T varijante (OR 5,53; P=0,13)...sr
dc.description.abstractProthrombin (Factor II) is a precursor of thrombin, one of the key regulatory enzymes in the maintainance of haemostasis. Elevated level of prothrombin leads to haemostatic disbalance and hypercoagulation, which can manifest as thrombotic disorders. The 3end of the prothrombin gene has noncanonical architecture that is sensitive to gain-of-function mutations, leading to increased prothrombin expression and elevated risk for thrombophilia. In our previous study we detected a novel C to T point mutation at the position 20068 in the last exon of the prothrombin gene. This gene variant leads to exchange of CGC to CGT codon which both code for arginine at the position 608 in the protein. C20068T gene variant is clasified as synonymous gene variant, under reference SNP ID number 3136532. This variant was more frequent in the patients with thrombosis compared to controls and leads to increased prothrombin mRNA expression. The first aim of this study was to determine the prevalence of C20068T gene variant in patients with thrombophilia, as well as in healthy controls. The second aim of this study was to elucidate the mechanism by which C20068T variant affects the prothrombin gene expression and pathogenesis of thrombophilia. This study included 797 subjects, divided in study and control groups. Patients were divided in five groups, according to thrombotic event they suffered from: 443 with several thrombotic manifestations, including 106 patients with cerebrovascular insult, 101 patient with pulmonary embolism, 175 patients with deep vein thrombosis and 61 patient with combined thrombotic events. This study also included 163 women who suffered from foetal losses. In the groups of patients with cerebrovascular insult, we have detected three heterozygous carriers of C20068T variant (OR 5.53; P=0.13), as well as in the group of patients with isolated pulmonary embolism (OR 5,81; P=0,12. In patients with deep vein thrombosis, 6 carriers of 20068CT genotype were detected (OR 6.74; P=0.057. Three heterozygous carriers were detected in the patients with combined thrombotic manifestations (OR 9.83; P=0.045). Our results indicate that C20068T represents significant risk factor for thrombotic occurence (OR 6.66; P=0.049)...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectprotrombinsr
dc.subjectprothrombinen
dc.subject3kraj protrombinskog genasr
dc.subjectgenska varijanta C20068Tsr
dc.subjectsinonimna genska varijantasr
dc.subjectregulacija ekspresijesr
dc.subjecttrombofilijasr
dc.subject3end of the prothrombin geneen
dc.subjectC20068T gene varianten
dc.subjectsynonymous gene varianten
dc.subjectgene expression regulationen
dc.subjectthrombophiliaen
dc.titleFunkcionalna analiza genske varijante C20068T u 3' kraju gena za protrombin čoveka i njena uloga u patogenezi trombofilijesr
dc.titleThe functional analysis of the C20068T gene variant in the 3' end of the prothrombin gene and its role in the pathogenesis of thrombophiliaen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractЂорђевић, Валентина; Томић, Бранко; Ковач, Мирјана; Радојковић, Драгица; Савић-Павићевић, Душанка; Прунер, Ива Б.; Функционална анализа генске варијанте Ц20068Т у 3' крају гена за протромбин човека и њена улога у патогенези тромбофилије; Функционална анализа генске варијанте Ц20068Т у 3' крају гена за протромбин човека и њена улога у патогенези тромбофилије;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/3124/Disertacija3647.pdf


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