Browsing by Author "Bundalo, Maja (55672084500)"

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.

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.