Pomen genskih polimorfizmov oksidacijskega stresa pri aterosklerozi vratnih arterij bolnikov s sladkorno boleznijo tipa 2

Marija Šantl-Letonja (Author), Danijel Petrovič (Mentor)

Abstract

Ateroskleroza je eden glavnih vzrokov obolevnosti in umrljivosti v razvitem svetu. Ateroskleroza karotidnih arterij je kazalnik sistemske ateroskleroze in izvor embolizmov, ki povzročijo prehodno ishemično atako ali možgansko kap. Oksidativni stres igra pomembno vlogo pri patogenezi skadkorne bolezni tipa 2 (SB), ki jo označujeta pospešen razvoj mikro- in makrovaskularnih zapletov. Miokardni infarkt in možganska kap se pri bolnikih s SB pojavljata do 4-krat pogosteje kot pri bolnikih brez SB in sta povezana z večjim številom zapletov in večjo umrljivostjo. Povečane dovzetnosti za aterosklerozo pri bolnikih s SB ne moremo v celoti pojasniti samo s pomočjo klasičnih dejavnikov tveganja. Stopnja oksidativnega stresa se pri posameznikih razlikuje in je vsaj delno genetsko pogojena. Genetski označevalci, ki so vpleteni v oksidativni stres, bi lahko igrali pomembno vlogo pri aterosklerozi karotidnih arterij pri bolnikih s SB. Postavili smo hipotezo, da genetski dejavniki, ki povečujejo oksidativni stres, vplivajo na nastanek ateroskleroze karotidnih arterij pri bolnikih s SB. Z asociacijsko raziskavo smo želeli ugotoviti, ali obstaja povezava med polimorfizmom +35A/C gena za SOD1, polimorfizmom Val16Ala gena za SOD2, polimorfizmom Gly/Arg gena za SOD3, polimorfizmom -262 C/T gena za katalazo, polimorfizmom Ile105Val gena za GSTP1, polimorfizem genov za GSTM1 in GSTT1, polimorfizmom 242 C/T gena za p22phox NAD(P)H, polimorfizmom -463A/G gena za mieloperoksidazo, polimorfizmom 4a/b gena za eNOS in polimorfizmom 277 A/G gena za iNOS in aterosklerozo karotidnih arterij pri bolnikih s SB. V presečno raziskavo smo vključili 287 bolnikov s SB tipa 2 in 158 zdravih oseb, ki so bile po spolu in starosti primerljive s preiskovanci s SB. Na ta način smo dobili referenčno skupino za primerjavo debeline intime in medije (DIM) v Pomurju. Preiskovancem smo opravili dvojno barvno dopplersko preiskavo karotidnih arterij in biokemijske preiskave s standardnimi bio-kemijskimi postopki. Vsi preiskovanci so bili slovanskega porekla in niso bili v sorodu. Poli-morfizme smo testirali s pomočjo verižne reakcije s polimerazo, s pomočjo multipleks reakcije PCR in z metodo PCR v realnem času. V pomurski populaciji je DIM pri bolnikih s SB značilno večja kot v zdravih preiskovancih brez diabetesa (1,09 ± 0,12 mm vs. 0,98 ± 0,14 mm; P=0,001). Pri bolniki s SB smo ugotovili, da je ničelni alel GSTT1-0 gena za GSTT1 tvegani alel za večji seštevek plakov na karotidnih arterijah. Genotip TT polimorfizma C242T gena za p22phox NAD(P)H je zaščitni genotip pred aterosklerozo karotid pri bolnikih s SB tipa 2 v Pomurju. Genotip bb polimorfizma 4a/b v intronu 4 gena za eNOS je tvegani genotip za visoki seštevek plakov. Z multivariatno regresijsko analizo smo ugotovili, da imajo nosilci alela T polimorfizma -262 C/T gena za katalazo pomembno nižjo nevarnost tveganja za visok seštevek plakov kot nosilci alela C. Z asociacijsko raziskavo nismo ugotovili povezave med polimorfizmi +35A/C gena za SOD1, Val16Ala gena za SOD2, Gly/Arg gena za SOD3, Ile105Val gena za GSTP1, -463A/G gena za mieloperoksidazo, gena za GSTM1, gena za GSTT1 in 277 A/G gena za iNOS ter aterosklerozo karotidnih arterij pri bolnikih s SB. Z rezultati raziskave smo dobili podatke, ki bodo doprinesli k boljšemu razumevanju pomena genetskih in biokemijskih dejavnikov tveganja pri nastanku ateroskleroze karotid, prav tako pa tudi potrjujejo njihovo pomembno vlogo pri strukturi plakov in razširjenosti plakov pri bolnikih s sladkorno boleznijo tipa 2.

Keywords

sladkorna bolezen;karotidna ateroskleroza;klasični dejavniki tveganja za srčnožilna obolenja;debelina intime - medije;seštevek plakov;debelina plakov;oksidativni stres;polimorfizmi genov oksidativnega stresa;Cu/Zn superoksidna dismutaza;Mn superoksidna dismutaza;zunajcelična superoksidna dismutaza;katalaza;mieloperoksidaza;glutationska transferaza;NAD(P)H-oksidaza;endotelna dušikova oksidaza;inducibilna dušikova oksidaza;

Data

Language:	Slovenian
Year of publishing:	2012
Typology:	2.08 - Doctoral Dissertation
Organization:	UM MF - Faculty of Medicine
Publisher:	M. Šantl Letonja]
UDC:	616.379-008.64-06(043.3)
COBISS:	7868211
Views:	4457
Downloads:	321
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Other data

Secondary language:	English
Secondary title:	ǂThe ǂrole of gene polymorphisms of oxidative stress in atherosclerosis of carotid arteries in patients with type2 diabetes
Secondary abstract:	Atherosclerosis is a major cause of morbidity and mortality in developed countries. Atherosclerosis of carotid arteries is an indicator of systemic atherosclerosis. Moreover, carotid atherosclerosis may be a cause of transitory ischemic attack or ischemic stroke. Oxidative stress is an important factor in pathogenesis of type 2 diabetes and it might be involved in the pathogenesis of microvascular and macrovascular complications. Myocardial infarction and ischemic stroke are 4 times more prevalent in diabetes in comparison with general population. Moreover, both disorders are associated with higher complication rate and mortality in diabetics in comparison with general population. Accelerated atherosclerosis in in type 2 diabetes can not be adequately explained with classical risk factors. It is speculated that oxidative stress may be involved in the pathogenesis of carotid atherosclerosis via effect on different risk factors. Our hypothesis was that genetic factors of oxidative stress might be involved in the development of atherosclerosis of carotid arteries in patients with type 2 diabetes. 287 patients with type 2 diabetes and 158 control subjects were enrolled in this cross sectional study. All subjects were Caucasians of Slovanic origin and they were from independent families. The normal carotid intima media thickness (CIMT) was defined in general population in Prekmurje (reference or control group). Biochemical analysis and Doppler colour code of carotid arteries were preformed in all subjects. In this study several polymorphisms were analysed in subjects with type 2 diabetes and healthy control: SOD1 +35A/C gene polymorphism, SOD2 Val16Ala gene polymorphism, SOD3 Gly/Arg gene polymorphism, catalase -262 C/T gene polymorphism, glutatione S-transferase (GSTP) P1 105Val gene polymorphism, polymorphisms of the GSTM1 and GSTT1 genes, p22phox NAD(P)H 242 C/T gene polymorphism, -463A/G gene polymorphism of mieloperoksidase, eNOS 4a/b gene polymorphism and iNOS 277 A/G gene polymorphism. Genotypes were deter-mined by polymerase chain reaction technique. CIMT in diabetics was higher in comparison with general population in Pomurje (1.09 ± 0.12 mm vs. 0.98 ± 0.14 mm; P=0.001). After adjustment for age, sex, smoking, BMI, lipid parameters and duration of hypertension and diabetes carriers of GSTT1-0 genotype showed an increased risk for higher plaque score (OR=2.29; p=0.012), but no association with CIMT and plaque stability was observed. Genotype TT of the p22phox NAD(P)H 242 C/T gene polymorphism was found to be protective against carotid atherosclerosis in subjects with type 2 diabetes. Genotype bb of the eNOS 4a/b gene polymorphism was found to be risk factor for higher plaque score in subjects with type 2 diabetes. The multivariate analysis demonstrated lower plaque score in carriers of T allele of 262 C/T catalase gene polymorphism. Polymorphisms +35A/C SOD1 gene, Val16Ala of SOD2 gene, Gly/Arg of SOD3 gene, GSTM1 and GSTP1 genes, 242 C/T of NAD(P)H gene, -463A/G of mieloperoksidase gene and A/G 277 of the iNOS gene were not associated with the atherosclerosis of carotid arteries in type 2 diabetes. Gene polymorphisms of oxidative stress may help us to elucidate the pathogenesis of carotid arteries in subjects with type 2 diabetes. With the study the important role of genes of oxidative stress in the pathogenenesis of carotid atherosclerosis in type 2 diabetes was confirmed.
Secondary keywords:	Sladkorna bolezen tip 2;Disertacije;Komplikacije;Karotidne arterije;Ateroskleroza;Oksidativni stres;Genetika;Genetski polimorfizem;
URN:	URN:SI:UM:
Type (COBISS):	Dissertation
Thesis comment:	Univ. v Mariboru, Medicinska fak.
Pages:	93 str.
ID:	8716785