Genetic polymorphism of glutathion S-transferase P1 (GSTP1) Ile105Val and susceptibility to atherogenesis in patients with type 2 diabetes mellitus

Abstract

One of the characteristics of type 2 diabetes mellitus (T2DM) is the state of persistent oxidative stress (OS) that has been implicated in the pathogenesis of diseases such is atherosclerosis mainly through chronic hyperglycemia that stimulates production of reactive oxygen species (ROS) and increases OS. Glutathione S-transferase P1 (GSTP1) is a member of the cytosolic GST superfamily. It plays an important role in neutralizing OS as an enzyme. Also, it participates in regulation of stress signaling and protects cells against apoptosis via its noncatalytic ligand-binding activity. GSTP1 Ile105Val functional polymorphism influences protein catalytic activity and stability and the aim of this study was to determine whether this gene variation influences susceptibility to atherogenesis in T2DM patients. A total of 240 individuals (140 patients with T2DM, accompanied with clinical manifestations of atherosclerosis, and 100 healthy controls) were included in this study. Genomic DNA was isolated from peripheral blood cells and genotyping was performed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) analysis. We obtained no statistically significant differences in the distribution of alleles and genotypes between cases and controls (P>0.05) but association between Ile/Val (OR=0.6, 95%CI=0.35-1.05, P=0.08) and Val/Val (OR=0.45, 95%CI=0.18-1.11, P=0.08) genotypes and disease approached significance (P=0.08). Our results indicated that a larger study group is needed to establish the true relationship between potentialiy protective allele Val and the disease, and to determine the influence of other GSTP1 polymorphisms on atherogenesis in T2DM patients.

Jedna od osobina tipa 2 dijabetes mellitus (T2DM) je stanje perzistentnog oksidativnog stresa (OS) koji je sastavni deo patogeneze bolesti kao što je ateroskleroza i to najčešće putem hronične hiperglikemije koja stimuliše nastanak reaktivnih vrsta kiseonika (tzv ROS) i povećava nivo OS. Glutation S-transferaza P1 (GSTP1) pripada superfamiliji citosolnih GST. Kao enzim, ima važnu ulogu u neutralizaciji OS. Takođe, učestvuje u regulaciji signalnog puta stresa ali i štiti ćelije od apoptoze putem nekatalitičke ligand-vezujuće aktivnosti. Funkcionalni polimorfizam Ile105Val GSTP1 gena utiče na katalitičku aktivnost proteina i na njegovu stabilnost i cilj ove studije je bio da se utvrdi da li ova genska varijanta utiče na osetljivost na aterogenezu kod pacijenata sa T2DM. Ukupno 240 osobe (140 pacijenata sa T2DM i nekom od kliničkih manifestacija ateroskleroze i 100 zdravih kontrola) je bilo uključeno u ovu studiju. Genomska DNK je izolovana iz ćelija periferne krvi a genotipizacija je urađena primenom reakcije lančane polimeraze posle koje je urađena analiza dužine restrikcionih fragmenata (PCR-RFLP analiza). Nismo dobili statistički značajne razlike u raspodeli alela i genotipova između obolelih i kontrola (P>0.05) ali asocijacija između Ile/Val (OR=0.6, 95%CI=0.35-1.05, P=0.08) i Val/Val (OR=0.45, 95%CI=0.18-1.11, P=0.08) genotipova i bolesti se približila značajnosti (P=0.08). Naši rezultaati pokazuju da je potrebna veća grupa ispitanika da bi se utvrdila prava veza između potencijalno protektivnog alela Val i bolesti kao i da bi se utvrdio uticaj drugih polimorfizama gena GSTP1 na aterogenezu kod T2DM pacijenata.