Browsing by Author "Stanković, Aleksandra (7006485474)"

Background and Aims: The principal biologic effects of the renin-angiotensin system are mediated by activation of the AT1R receptor. The microRNA miR-155 regulates AT1R expression, with both its, and AT1R's activity, linked to atherosclerosis. Target sites for miR-155 lie within the 3' UTR of the human AT1R gene, and include the AT1R A1166C polymorphism. Thus far, only levels of circulating miR-155 have been investigated with respect to A1166C genotypes. We hypothesized that the A1166C polymorphism could correlate with different, ultra-sonographically defined plaque phenotypes, as well as with an altered expression of AT1R mRNA and protein in human carotid plaques (CP), and altered expression of miR-155 in patients with advanced atherosclerosis. Methods: Our study cohort comprised 411 patients with advanced carotid atherosclerosis (298 hyperechoic; 113 hypoechoic plaques). PCR analyses identified A1166C genotypes; quantitative real-time PCR determined AT1R and miR-155 expression levels, with AT1R protein expression evaluated by western blot. Results: Genotypes containing the C allele bore a significant association with the hypoechoic plaque phenotype (adjusted OR 1.87, 95% CI 1.16-3.00, p = 0.01). The expression of AT1R mRNA and miR-155 were significantly up-regulated in the CPs of CC genotype carriers compared to the AA/AC genotypes (p = 0.032, p = 0.015, respectively). AT1R protein expression was also significantly higher for CC genotypes (p < 0.01). Conclusion: Our results indicate that the AT1R A1166C polymorphism impacts an ultrasonographically-defined human plaque phenotype, with intra-plaque AT1R and miR-155 expression altered in advanced carotid atherosclerosis. Validation and replication of these data should contribute to an improved personalized therapy with which to prevent carotid atherosclerosis. © 2016 Elsevier Ireland Ltd.

Objective: Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix in the arterial wall. Collagen I is associated with vascular smooth muscle cell (VSMC) migration and monocyte differentiation. MMP-8 is expressed in atherosclerotic plaque and preferentially cleaves collagen type I. The aim of this study was to investigate the associations of two MMP-8 promoter polymorphisms, rs11225395 (-799. C/T) and rs1320632 (-381 A/G), with carotid plaque occurrence, and the influence of these polymorphisms on MMP-8 mRNA expression in plaque tissue. Methods: The study included a total of 766 participants: 277 controls and 489 patients with carotid atherosclerosis undergoing endarterectomy. The two investigated polymorphisms were genotyped by PCR-RFLP. The gene expression analysis was performed by real-time PCR. Results: In females only, a significantly higher frequency of the -381G allele was found in patients with carotid atherosclerosis compared to controls (OR, 1.7; 95% CI 1.1-2.9; p=0.001). Significant up-regulation of MMP-8 gene expression was observed in patients carrying the -381G allele compared to those with the AA genotype (mean factor, 3.54; S.E. range, 0.643-19.551; p=0.007). Carotid plaque tissue of the haplotype G -381T -799 showed a significantly higher mRNA level compared with the reference A -381C -799 haplotype (p=0.003). Conclusion: Our preliminary results indicate that MMP-8-381A/G and -799. C/T gene polymorphisms could be risk factors for carotid atherosclerosis. Further validation and functional studies are needed to establish the potential regulatory role of these polymorphisms and their impact on susceptibility to carotid atherosclerosis. © 2011 Elsevier Ireland Ltd.

Background: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR∗28). The aim of this study was to assess the impact of age, CYP3A5∗3, CYP3A4∗22, and POR∗28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. Methods: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5∗3, CYP3A4∗22, and POR∗28. Results: CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 6 12.75 versus 22.44 6 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR∗28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR∗1/∗1 genotype (165.54 6 70.40 versus 210.55 6 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 6 4.72 versus 34.19 6 11.89, P = 0.001) and C2/dose (106.75 6 26.99 versus 209.20 6 71.57, P < 0.001) compared with older children. Carriers of CYP3A5∗3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR∗28 allele aged #6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P, 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016). Conclusions: Younger age, POR∗28 allele, and CYP3A5∗3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR∗28). The aim of this study was to assess the impact of age, CYP3A5∗3, CYP3A4∗22, and POR∗28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. Methods: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5∗3, CYP3A4∗22, and POR∗28. Results: CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 6 12.75 versus 22.44 6 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR∗28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR∗1/∗1 genotype (165.54 6 70.40 versus 210.55 6 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 6 4.72 versus 34.19 6 11.89, P = 0.001) and C2/dose (106.75 6 26.99 versus 209.20 6 71.57, P < 0.001) compared with older children. Carriers of CYP3A5∗3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR∗28 allele aged #6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P, 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016). Conclusions: Younger age, POR∗28 allele, and CYP3A5∗3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background The angiotensin II type 2 receptor (AT2R) -1332 A/G polymorphism has been denoted as functional and associated with certain cardiovascular disease phenotypes. However, there are no studies considering the association of this gene polymorphism with carotid atherosclerosis (CA) and cerebrovascular events. Therefore, the aim of our study was to investigate a possible association of the AT2R -1332 A/G polymorphism with the occurrence of carotid plaques (CPs) and history of cerebrovascular insult (CVI) in advanced CA. Methods The study group included 381 controls and 509 patients with CA consecutively admitted for endarterectomy. Genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism method. The association was analyzed separately for males and females because the AT2R gene is located on the X chromosome. Results The AT2R -1332 GG genotype was associated with the advanced CA in the female study group (recessive model of inheritance, AA+AG versus GG; adjusted odds ratio [OR] = 2.25; 95% confidence interval [CI] 1.17-4.33; P =.01). In the male subgroup of patients with CA, the significant overrepresentation of G/- hemizygote was detected in patients with CVI compared to male patients without this event (crude OR = 2.05, 95% CI 1.20-3.50, P =.008). Conclusions This study suggests a gender-specific association between the AT2R -1332 A/G polymorphism and the occurrence of CP and the history of CVI in advanced CA, but further replication studies are needed. © 2016 National Stroke Association.

Objectives. Chronic otitis media (COM) is followed by irreversible tissue damage and destruction of the middle ear structures, with the possibility of complications under the maintenance of inflammation. Inflammatory mediators such as cytokines play a crucial role in the initial stage of inflammation. The aim of this study was to evaluate the association of the polymorphisms in two innate immunity/inflammation cascade genes from interleukin-1 (IL-1) gene cluster with COM with regard to cholesteatoma. Methods. In the cross-sectional case-control study, DNA samples were collected from 189 patients with COM and 119 controls from a population of Serbia. The +3953 C/T (rs1143634), TaqI polymorphism in interleukin-1 beta (IL-1Β) gene and 86 bp variable number tandem repeat (VNTR, rs2234663) polymorphism in the IL-1 receptor antagonist (IL-1RA) gene were analyzed by polymerase chain reaction. Results. The IL-1Β TaqI polymorphism was not significantly different in patients compared with the control group. The significant difference between patients and controls was observed for both, genotype and allele frequencies of IL-1RA VNTR polymorphism (chi-square P<0.01). We found that carriers of IL-1RA allele 2 (odds ratio, 0.47; 95% confidence interval, 0.29 to 0.76; P=0.004) have a favorable association with COM, using multivariate logistic analysis that included both polymorphisms, age and sex. The IL-1RA allele frequency distribution was significantly different with regard to cholesteatoma. Conclusion. The carriers of allele 2 of VNTR IL-1RA polymorphism had a decreased odds ratio for COM, which is in agreement with findings in other inflammatory disease and its previous association with higher IL-1RA levels. Possible down-regulation of IL-1 mediated proinflammatory signaling pathways via IL-1RA in COM as well as results of our study should be further investigated and replicated. © 2018 by Korean Society of Otorhinolaryngology-Head and Neck Surgery.

Introduction: The ACE I/D polymorphism was mostly investigated in association with intima-media thickness, rarely with severe atherosclerotic phenotype.Materials and methods: We investigated the association of I/D polymorphism with severe carotid atherosclerosis (CA) (stenosis > 70%) in asymptomatic and symptomatic patients undergoing carotid endarterectomy. The 504 patients subjected to endarterectomy and 492 healthy controls from a population in Serbia were investigated as a case-control study.Results: The univariate logistic regression analysis revealed ACE DD as a significant risk factor for severe CA (odds ratio [OR] = 1.3, 95% confidence interval [CI] 1.0-1.7, p = 0.04). After adjustment for the common risk factors (age, hypertension, smoking, and HDL) ACE was no longer significant. However, we found a significant independent influence of DD genotype on plaque presence in a normotensive subgroup of patients (OR 1.8, CI 1.2-3.0, p = 0.01, corrected for multiple testing). In symptomatic patients D allele carriers were significantly more frequent compared with asymptomatic patients (OR 1.6 CI 1.0-2.6, p = 0.05).Conclusions: Our data suggests that ACE I/D is not an independent risk factor for severe CA. On the other hand, a significant independent genetic influence of ACE I/D appeared in normotensive and symptomatic patients with severe CA. This should be considered in further research toward resolving the complex genetic background of severe CA phenotype. © The Author(s) 2011.

Introduction: The ACE I/D polymorphism was mostly investigated in association with intima-media thickness, rarely with severe atherosclerotic phenotype.Materials and methods: We investigated the association of I/D polymorphism with severe carotid atherosclerosis (CA) (stenosis > 70%) in asymptomatic and symptomatic patients undergoing carotid endarterectomy. The 504 patients subjected to endarterectomy and 492 healthy controls from a population in Serbia were investigated as a case-control study.Results: The univariate logistic regression analysis revealed ACE DD as a significant risk factor for severe CA (odds ratio [OR] = 1.3, 95% confidence interval [CI] 1.0-1.7, p = 0.04). After adjustment for the common risk factors (age, hypertension, smoking, and HDL) ACE was no longer significant. However, we found a significant independent influence of DD genotype on plaque presence in a normotensive subgroup of patients (OR 1.8, CI 1.2-3.0, p = 0.01, corrected for multiple testing). In symptomatic patients D allele carriers were significantly more frequent compared with asymptomatic patients (OR 1.6 CI 1.0-2.6, p = 0.05).Conclusions: Our data suggests that ACE I/D is not an independent risk factor for severe CA. On the other hand, a significant independent genetic influence of ACE I/D appeared in normotensive and symptomatic patients with severe CA. This should be considered in further research toward resolving the complex genetic background of severe CA phenotype. © The Author(s) 2011.