doktorska disertacija
Dražen Popovič (Author), Danijel Petrovič (Mentor), Ivan Krajnc (Thesis defence commission member)

Abstract

Ateroskleroza je kronično vnetno dogajanje, za katero je značilno nalaganje leh, sestavljenih iz penastih celic, celic imunskega sistema, celic vaskularnega endotelija, ravnih mišičnih celic, trombocitov, zunajceličnega matriksa in z maščobami bogatega jedra z nekrozami in s fibroznim okolnim tkivom. Zapleti ateroskleroze so glavni vzrok obolevnosti in smrti v razvitem svetu. Sladkorna bolezen je pomemben dejavnik tveganja za razvoj ateroskleroze. Ključno patološko dogajanje pri aterosklerozi je poškodba endotelija arterijske stene oziroma vnetni odgovor, ki ga poškodba sproži. Poškodba spodbudi endotelijske celice k izločanju vazoaktivnih in adhezijskih molekul, citokinov in rastnih dejavnikov. Ugotovljena je zvišana raven adhezijskih molekul pri bolnikih z napredovalo aterosklerozo in s sladkorno boleznijo. Pomembna v razvoju ateroskleroznih sprememb bi lahko bila vloga genskih označevalcev, vpletenih v vnetni odgovor. Postavili smo hipotezo, da genski označevalci, ki uravnavajo vnetni odgovor, vplivajo na nastanek ateroskleroznih sprememb in napredovanje ateroskleroze karotidnih arterij pri bolnikih s sladkorno boleznijo tipa 2 (SB tipa 2). Z asociacijsko raziskavo smo ugotavljali povezavo med polimorfizmom K469E (rs 5498) gena za ICAM 1, polimorfizmom G241A (rs 1799969) gena za ICAM 1, polimorfizmom C373G (Leu125Val, rs 668) gena za PECAM 1, polimorfizmom –1082 G/A (rs18000896) gena za interlevkin 10 (IL 10), polimorfizmom –1159 A/C (rs3212227) gena za interlevkin 12 (IL 12), polimorfizmom –607 C/A (rs1946518) gena za IL 18 in polimorfizmom –137 G/C (rs187238) gena za IL 18 ter ultrazvočnimi označevalci ateroskleroze, napredovanjem ultrazvočnih označevalcev ateroskleroze in stabilnostjo leh v vratnih arterijah. V raziskavo smo vključili 795 preiskovancev; 595 je bilo bolnikov s SB tipa 2 in 200 preiskovancev v kontrolni skupini brez SB tipa 2. Preiskovanci so bili slovenskega rodu in niso bili v sorodu. Odvzeli smo jim kri za biokemijske in molekularnogenetske preiskave ter izvedli doplersko preiskavo karotidnih arterij. Preiskovanci so izpolnili vprašalnik z anamnestičnimi podatki. Primerjava ultrazvočnih označevalcev ateroskleroze je pokazala statistično pomembno višje vrednosti v debelini intime in medije (DIM) karotidnih arterij (p = 0,03), v seštevku debeline leh (p = < 0,001) in v številu segmentov z lehami (p = 0,01) v skupini bolnikov s SB tipa 2. Prav tako so bile statistično pomembno višje vrednosti pri kontrolnem pregledu v letnem prirastku DIM karotidnih arterij (p = 0,02), Δ števila segmentov z lehami (p = 0,03) in Δ seštevka debeline leh (p = 0,02) v skupini bolnikov s SB tipa 2. Ugotovili smo povezavo med genotipom EE K469E (rs5498) polimorfizma za ICAM 1 in višjo vrednostjo seštevka debeline leh (p = 0,04), prisotnostjo nestabilnih leh (p = 0,01) in večjim letnim prirastkom DIM karotidnih arterij (p = 0,04) pri bolnikih s SB tipa 2. Rezultati niso pokazali statistično pomembne povezave med ultrazvočnimi označevalci ateroskleroze in genotipi polimorfizma G241A (rs1799969) gena za ICAM 1 pri bolnikih s SB tipa 2. Statistično pomembna razlika je bila ugotovljena med genotipom GG polimorfizma C373G (rs668) gena za PECAM 1 in prisotnostjo leh v karotidni arteriji (p = 0,03). Genotipi polimorfizma rs668 gena za PECAM 1 na druge ultrazvočne označevalce ateroskleroze niso vplivali enako kot na napredovanje ateroskleroznih sprememb. Za genotipa GA in AA polimorfizma G1082A (rs1800896) gena za IL 10 so bile značilne statistično pomembno stabilnejše lehe glede na genotip GG (p = 0,03). Genotipi polimorfizma rs1800896 gena za IL 10 na druge ultrazvočne označevalce ateroskleroze karotidne arterije niso vplivali enako kot na napredovanje ateroskleroze. V raziskavi nismo ugotovili povezave med ultrazvočnimi označevalci ateroskleroze in genotipi polimorfizma C1159A (rs3212227) gena za IL 12 pri bolnikih s SB tipa 2. Prav tako nismo ugotovili povezave med genotipi polimorfizma C607A (rs1946518) in G137C (rs187238) gen

Keywords

progresija;endotelij;celične adhezijske molekule;biološki označevalci;genetski označevalci;vnetni odziv;interlevkini;molekularna genetika;

Data

Language: Slovenian
Year of publishing:
Typology: 2.08 - Doctoral Dissertation
Organization: UM MF - Faculty of Medicine
Publisher: D. Popović]
UDC: 616.379-008.64-06(043.3)
COBISS: 289946624 Link will open in a new window
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Secondary language: English
Secondary title: Gene polymorphisms of adhesion molecules and proiflammatory genes and progression of atherosclerosis of carotid arteries in patients with diabetes mellitus Type 2
Secondary abstract: Atherosclerosis is a chronic inflammatory process that is characterized by the formation of atherosclerotic plaque consisting of foam cells, immune cells, vascular endothelium cells, smooth muscle cells, platelets, the extracellular matrix with a lipid-rich core with necrosis and fibrosis of surrounding tissues. Complications resulting from atherosclerosis are the leading cause of morbidity and mortality in the developed world. Diabetes mellitus is one of the major risk factors for the development of atherosclerosis. The key pathological events in atherosclerosis are endothelial dysfunction and the inflammatory response to endothelial injury. Endothelial dysfunctions induce the secretion of vasoactive and adhesion molecules, cytokines and growth factors. Elevated levels of adhesion molecules in patients with advanced atherosclerosis and diabetes mellitus were established. Genetic markers, which are involved in the inflammatory response, could have an important role in the development of atherosclerosis. Our hypothesis was that genetic markers influence the inflammatory response through the stimulation of atherosclerotic changes and the progression of atherosclerosis in the carotid arteries of patients with diabetes mellitus type 2. With an associative study we investigated the association between polymorphism K469E (rs 5498) gene for ICAM-1, polymorphism G241A (rs1799969) gene for ICAM-1, polymorphism C373G (Leu125Val, RS 668) gene for PECAM-1, polymorphism -1082 G / A (rs18000896) gene for interleukin-10 (IL-10), polymorphism -1159 A / C (rs3212227) gene for interleukin-12 (IL-12), polymorphism -607 C / A (rs1946518) gene for IL-18 and polymorphism -137 G / C (rs187238) gene for IL-18 and ultrasonographic markers of atherosclerosis, ultrasound markers of the progression of atherosclerosis and plaque stability in the carotid arteries. In this cross-sectional study, 795 subjects were enrolled, 595 patients with diabetes type 2 and 200 subjects in the control group without diabetes type 2. The subjects were of Slovenian origin and were not related. Blood samples were taken for biochemical and genetic tests and a Colour Doppler examination of the carotid arteries was made. The subjects completed a questionnaire including data on medical history. Our study showed statistically significant higher levels intima media thickness (IMT) of the carotid artery (p = 0.03), the sum of plaque thickness (p = < 0.001) and number of plaques segment (p = 0.01) in the group of patients with diabetes type 2. The study also demonstrated significantly higher values in the increment of IMT carotid artery (p = 0.02), Δ number of segments with plaques (p = 0.03) and Δ sum of plaque thickness (p = 0.02) in patients with diabetes type 2. We have established an association between genotype EE K469E (rs5498) polymorphism of ICAM-1 and the higher value of the sum plaque thickness (p = 0.04), the presence of unstable plaques (p = 0.01) and the maximum annual increment of carotid artery IMT (p = 0.04) in patients with diabetes type 2. The results of our study have not shown a statistically significant correlation between ultrasonographic markers of atherosclerosis and genotypes of G241A polymorphism (rs1799969) gene for ICAM-1 in patients with diabetes type 2. A statistically significant difference was found in the genotype GG C373G (rs668) polymorphism gene for PECAM-1 in the presence of plaques at the carotid artery (p = 0.03). The genotypes of polymorphism of rs668 gene for PECAM-1 have not had the same influence on other ultrasound markers of atherosclerosis than they have had on the progression of atherosclerotic changes. Subjects with genotype GA and AA had the statistically significant more stable plaques with respect to the plaque genotype GG G1082A (rs1800896) polymorphism gene for IL-10 (p = 0.03). The genotypes of polymorphism of rs1800896 gene for IL 10 have not had the same influence on other ultrasound markers of the carotid artery than t
Secondary keywords: Sladkorna bolezen tip 2;Disertacije;Komplikacije;Karotidne arterije;Ateroskleroza;Genetski polimorfizem;
URN: URN:SI:UM:
Type (COBISS): Dissertation
Thesis comment: Univ. v Mariboru, Medicinska fak.
Pages: 98 f.
ID: 9136528