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Analysis of variants in the promoter region of CYP2C19 gene and their role in prediction of clopidogrel response in patients with myocardial infarcition and carotid stenosis

dc.contributor.advisorRakićević, Ljiljana
dc.contributor.otherSavić-Pavićević, Dušanka
dc.contributor.otherRadojković, Dragica
dc.contributor.otherBrajušković, Goran
dc.contributor.otherAntonijević, Nebojša
dc.creatorNovković, Mirjana
dc.date.accessioned2019-01-31T12:45:46Z
dc.date.available2019-01-31T12:45:46Z
dc.date.issued2018-11-20
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6572
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:19349/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025209010
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/10712
dc.description.abstractKlopidogrel je antiagregacioni lek koji je sa aspirinom, u sklopu dvojne antiagregacione terapije, indikovan u stanjima koja nose rizik od ishemijskih događaja i tromboembolijskih komplikacija. Postoji velika interindividualna varijabilnost u odgovoru na klopidogrel. Značajan broj pacijenata kao posledicu neadekvatnog odgovora na terapiju može iskusiti različita neželjena dejstva. Kod oko 9% pacijenata koji su na terapiji klopidogrelom javlja se krvarenje kao neželjeni efekat. Ono samo po sebi može biti životno ugrožavajuće, a sekundarno može biti povezano sa pojavom ishemijskih događaja. Uzroci varijabilnosti u odgovoru na terapiju klopidogrelom, mogu biti kako stečeni, tako i posledica genetičkih faktora. Među genetičkim faktorima najznačajniji doprinos ima gen za enzim CYP2C19 koji je neophodan u procesu konverzije klopidogrela u aktivnu formu leka. Zbog toga su varijante CYP2C19 gena najčešće razmatrane u okviru farmakogenetike klopidogrela. Od posebnog kliničkog značaja su varijante rs4244285 (c.681G>A; CYP2C19*2) i rs4986893 (c.636G>A; CYP2C19*3), koje su povezane sa oslabljenim odgovorom na klopidogrel. Promotorska varijanta rs12248560 (c.-806C>T, CYP2C19*17) se dovodi u vezu sa pojačanim stepenom inhibicije trombocita i povišenim rizikom od krvarenja kod pacijenata na terapiji klopidogrelom. U fokusu ove studije bilo je ispitivanje uticaja CYP2C19 gena na pojavu pojačanog odgovora na klopidogrel koje vodi povišenom riziku od krvarenja. Istraživanje je sprovedeno u grupi pacijenata koji su pretrpeli infarkt miokarda i bili podvrgnuti perkutanoj koronarnoj intervenciji (PCI), kao i grupi pacijenata sa stenozom karotida koji su podvrgnuti karotidnoj endarterektomiji (CEA). U studiji su analizirane promotorske varijante rs12248560 (c.-806C>T, CYP2C19*17) i rs11568732 (c.-889T>G, CYP2C19*20) za koje su literaturni podaci i naši preliminarni rezultati pokazali da mogu biti povezane sa pojačanim odgovorom na klopidogrel. Dodatno su analizirane egzonske varijante rs4244285 (c.681G>A; CYP2C19*2) i rs4986893 (c.636G>A, CYP2C19*3) zbog mogućeg uticaja na efekte promotorskih varijanti. Zbog oskudnosti podataka koji se odnose na promotorsku varijantu rs11568732 (c.-889T>G, CYP2C19*20), jedan od ciljeva studije bio je da se u in vitro uslovima ispita njen funkcijski značaj...sr
dc.description.abstractWide inter-individual variability in clopidogrel response has been reported. Significant number of patients with inadequate response to clopidogrel experience different adverse effects. Bleeding as an adverse event occurs in about 9% of patients on clopidogrel therapy. It can be life threatening and secondarily, related to higher risk of ischemic events. Variability in clopidogrel response may be explained by different non-genetic and genetic factors. Among genetic factors, the most important role has CYP2C19 gene encoding enzyme responsible for conversion of clopidogrel to its active form. Hence, CYP2C19 gene variants are the most commonly investigated genetic variants related to clopidogrel pharmacogenetics. Clinically, the most relevant variants are rs4244285 (c.681G>A; CYP2C19*2) and rs4986893 (c.636G>A; CYP2C19*3) which lead to clopidogrel poor response. Additionally, promoter variant rs12248560 (c.-806C>T, CYP2C19*17) is associated with elevated platelet inhibition and increased risk of bleeding in patients on clopidogrel. This study was focused on investigating role of CYP2C19 gene in clopidogrel hyper-responsiveness which increases the risk of bleeding. This study was conducted in a group of patients with acute myocardial infarction who underwent percutaneous coronary intervention (PCI) as well as in patients with carotid stenosis who underwent carotid endarterectomy (CEA). In this study we examined two promoter rs12248560 (CYP2C19*17) and rs11568732 (CYP2C19*20) variants, for which literature and our preliminary results showed to be associated with elevated clopidogrel response. Additionally, we analyzed exonic variants rs4244285 (c.681G>A; CYP2C19*2) and rs4986893 (c.636G>A, CYP2C19*3) considering their potential influence on the promoter variants’ effects. Since literature data on rs11568732 (c.-889T>G, CYP2C19*20) variant is scarce, we aimed to investigate its functional significance. Further, one of our aims was the anlysis of the relevant CYP2C19 variants regarding clopidogrel therapy, which can be used to rationalize current protocols for antiplatelet therapy in Serbia...en
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dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173008/RS//
dc.rightsAutorstvo-Nekomercijalno-Bez prerade 3.0 Srbija (CC BY-NC-ND 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectgenske varijante , CYP2C19, klopidogrel, krvarenje, ADP-indukovana agregacija trombocita, infarkt miokarda, stenoza karotida, farmakogenetikasr
dc.subjectgenetic variants, CYP2C19, clopidogrel, bleeding, ADP induced platelet aggregation, myocardial infarction, carotid stenosis, pharmacogeneticsen
dc.titleAnaliza promotorskih varijanti genaCYP2C19 i njihova uloga u predviđanju terapijskog odgovora na lek klopidogrel kod pacijenata sa infarktom miokarda i stenozom kariotidasr
dc.title.alternativeAnalysis of variants in the promoter region of CYP2C19 gene and their role in prediction of clopidogrel response in patients with myocardial infarcition and carotid stenosisen
dc.typePhD thesis


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