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Association of genetic variants in chromoseome 9p21 and transcription of CDKN2B and HACD4 genes with the onset of atherosclerosis and its clinical complications in human.

dc.contributor.advisorŽivković, Maja
dc.contributor.otherBrajušković, Goran
dc.contributor.otherĐurić, Tamara
dc.contributor.otherŽivković, Maja
dc.contributor.otherBrajušković, Goran
dc.creatorŽivotić, Ivan
dc.date.accessioned2019-11-15T12:36:56Z
dc.date.available2019-11-15T12:36:56Z
dc.date.available2020-07-03T08:07:56Z
dc.date.issued2019-05-14
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/11534
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=6931
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:20301/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025217714
dc.description.abstractAteroskleroza je kompleksna, hronična i progresivna bolest arterijskih krvnih sudova koja se razvija tokom života i najčešće se klinički manifestuje u kasnijem životnom dobu. Dve najznačajnije kliničke komplikacije su ishemijski moždni i srčani udar (IM), na čiji nastanak utiču sredinski i nasledni faktori (genetska predispozicija). U ovoj studiji ispitana je asocijacija četiri genetičke varijante prisutne u hromozomskom regionu 9p21 (rs10757278 i rs518394 u genu ANRIL, i rs36212560 i rs2275888 u genu HACD4), sa rizikom za nastanak IM, karotidnog plaka (KP) i kliničkih komplikacija KP (ultrasonografski definisan tip plaka, simptomatska karotidna bolest, prisustvo ulceracije na plaku). Ispitana je transkripcija gena CDKN2B i HACD4 kao i nivo iRNK u tkivu karotidnog aterosklerotskog plaka i mononuklearnim ćelijama periferne krvi (MĆPK) bolesnika koji su doživeli prvi IM, 6 meseci nakon infarkta. Nivo iRNK ispitan je u odnosu na genotipove i tip karotidnog plaka. Utvrđena je značajna asocijacija rs10757278 sa rizikom za nastanak KP kod žena. Utvrđeno je da je haplotip genetičkih varijanti rs36212560 i rs2275888 značajno asociran sa rizikom za nastanak KP i IM. Rezutlat je pokazao polno specifičnu asocijaciju (kod muškaraca) kao i značajnu asocijaciju varijante rs36212560 testirane van haplotipa. Nije detektovana značajna asocijacija genetičkih varijanti rs2275888 i rs518394 sa rizikom za razvoj karotidnog plaka, ali je ustanovljena značajna, nezavisna asocijacija varijante rs2275888 sa rizikom za nastanak IM. Varijanta rs10757278 je značajno asocirana sa tipom karotidnog aterosklerotskog plaka. Ustanovljeno je da je haplotip varijanti rs36212560 i rs2275888 značajno asociran sa rizikom za razvoj ulceracije karotidnog plaka, i sa simptomatskom karotidnom bolešću u grupi bolesnika sa KP, kao i da polno specifična asocijacija sa haplotipom postoji kod muškaraca. Razlika u nivoima ekspresije merena je na nivou iRNK u odnosu na genotipove ispitivanih varijanti. U tkivu KP nije detektovana razlika u nivou iRNK za CDKN2B u odnosu na genotipove ispitivanih varijanti, ali je ustanovljen statistički trend u asocijaciji sa genotipom varijante rs1075278. Varijanta rs2275888 je prethodno okarakterisan kao eQTL (eng. expression Quantitative Trait Locus) za gen FOCAD gen u tibijalnoj arteriji...sr
dc.description.abstractAtherosclerosis is a complex, chronic and progeressive disease of arterial blood vessels that develops during the life and usualy with clinical manifestations at later age. Two most singnifficant clinical manifestations are stroke and myocardial infarction (MI), which development is affected by the median and hereditary factors (genetic predisposition). In this study, association of four genetic variants from chromosome region 9p21 have been investigated (rs10757278 and rs518394 in the ANRIL gene, and rs36212560 and rs2275888 in the HACD4 gene) with the risk for development of MI, the carotid plaque (CP) and its clinical complications (ultrasonographicaly deffined plaque type, symphtomatic disease, presence of carotid plaque ulceration). The transcription of genes CDKN2B and HACD4 at the mRNA level was examined in the CP tissue and peripheral blood mononuclear cells (PBMC) of patients who sustained first MI, six months after the infarction. Level of mRNA was examined in relation to genotypes and CP type. Signifficant association was determined for rs10757278 with the risk for CP development among females. It was determined that haplotype of gene variants rs36212560 and rs2275888 is significantly associated with the risk for CP and MI development. Result has shown gender specific association (among males) as well as association of rs36212560 with CP and MI when tested independently. It wasn’t detected signifficant association of gene variants rs2275888 and rs518394 with the risk for the development of CP, but, the signifficant idependant association of rs2275888 variant with the risk for MI. Variant rs10757278 is signifficantly associated with the carotid atherosclerotic plaque type. Haplotype of rs36212560 and rs2275888 variants is signifficantly associated with the carotid plaque ulceration, as well as with simpthomatic carotid disease in the group of CP patients., and in addition, the gender speciffic association with the haplotype exist in males. Diference in expression levels was measured at the level of mRNA in relation to genotypes of tested variants. In CP tissue difference in CDKN2B mRNK level wasn’t detected in relation to tested variants according to genotype, but statistical trend was detected in association with rs10757278 genotypes...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41028/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectstudija asocijacijesr
dc.subjectassociation studyen
dc.subjectgenetic variantsen
dc.subjectcarotid plaque (CP)en
dc.subjectmyocardial infarction (MI)en
dc.subject9p21en
dc.subjectCDKN2Ben
dc.subjectHACD4en
dc.subjectFOCADen
dc.subjectmRNKen
dc.subjectgenetičke varijantesr
dc.subjectkarotidni plaksr
dc.subjectinfarkt miokardasr
dc.subject9p21sr
dc.subjectCDKN2Bsr
dc.subjectHACD4sr
dc.subjectFOCADsr
dc.subjectiRNKsr
dc.subjectrelativna ekspresijasr
dc.titleAsocijacija genskih varijanti na hromozomu 9p21 i transkripcije gena za CDKN2B i HACD4 sa nastankom ateroskleroze i njenim kliničkim komplikacijama kod čovekasr
dc.title.alternativeAssociation of genetic variants in chromoseome 9p21 and transcription of CDKN2B and HACD4 genes with the onset of atherosclerosis and its clinical complications in human.en
dc.typedoctoralThesis
dc.rights.licenseBY
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1740/IzvestajKomisije21142.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1739/Disertacija.pdf


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