Репозиторий Университета

© 2019, Italian Society of Hypertension. Introduction: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. Aim: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. Methods: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. Results: The study revealed the following haplotypes: (1) ABCB1 rs1045642—CYP3A4 rs35599367 and (2) ABCB1 rs4148738—CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). Conclusion: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.

Rheumatoid arthritis (RA) is a multifactorial disease, in which the interaction of the genetic component and environmental factors, determines not only the development of the disease, but also its pronounced clinical polymorphism. We assume that the high inflammatory activity of RA may be determined by the genes, the products of which trigger inflammatory processes. Objective: to investigate allele and genotype distribution of gene polymorphic variants in active anti-cyclic citrullinated peptide (aCCP)-positive patients with RA from the REMARCA program versus a control group of healthy blood donors. Subjects and methods. A molecular genetic study enrolled 146 aCCP-positive patients from the REMARCA program and a control group of 314 healthy blood donors without autoimmune diseases and their presence in the history, who were matched with the study group for gender and sex. The polymorphic variants of the genes PTPN22 (+1858C>T, rs2476601), TNFAIP3 (rs6920220, rs10499194), CTLA4 (+49A>G, rs231775), TNF? (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -892 C>T, rs1800871, -1082 A>G, rs1800896), and MCP1/CCL2 (+2518A>G, rs1024611) were genotyped by a real-time polymerase chain reaction assay. Results and discussion. The genotype and allele frequencies of polymorphic variants of the genes CTLA4 (+49A>G), IL-6R (+358A>C), and IL10 (- 592A>C) in the RA group significantly differed from those in the control group. When comparing with the control group, the minor alleles of the CTLA4 and IL10 genes were markers for the risk of aCCP-positive RA with a high inflammatory activity (OR=1.4 [1.1; 1.9], p=0.02 and OR=1.9 [1.4; 2.5]; p=0.0001, respectively). At the same time, the minor C allele of the IL6R gene served as a marker of protection (OR=0.7 [0.5; 0.9]; p=0.03). Logistic regression analysis revealed that there was a statistically significant correlation of the high inflammatory activity indices SDAI, CDAI, and DAS28 with the minor homozygous GG genotype of the CTLA4 gene (OR=2.5 [1.1; 6.0]; p=0.03, OR=2.6 [1.1–6.4], p=0.03 and OR=3.4 [1.3–8.8]; p=0.01, respectively). In addition, the inflammatory activity indices SDAI and CDAI rather than DAS28-ESR were associated with at least one minor A allele (the AA/AC genotypes) of the IL10 gene (OR=2.4 [1.2; 5.1], p=0.02 and OR=2.2 [1.1; 4.7]; p=0.03, respectively). The levels of ESR and CRP were not associated with the examined polymorphisms. Conclusion. The findings may suggest that there is a relationship of the polymorphisms of the genes CTLA4 (+49A>G, rs231775), IL6R (+358A>C, rs8192284), and IL10 (-592A>C, rs1800872) to high inflammatory activity in the group of aCCP-positive patients from the REMARCA study.