Browsing by Author "Darai, Masumeh"

Now showing 1 - 6 of 6

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population
(Başkent Üniversitesi, 2012-02) Rahsaz, Marjan; Aghdaie, Mahdokht H.; Banihashemi, Mehrzad; Malekhoseini, Seid Ali; Malekpour, Zahra; Darai, Masumeh; Moini, Maryam; Geramizadeh, Bita; Nikeghbalian, Saman; Azarpira, Negar
Objectives: Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein. Materials and Methods: We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T]. Results: Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found. Conclusions: Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.
Influence of Endothelial Nitric Oxide Synthase Gene Polymorphisms (-786T/C, 4a4b, 894G/T) on Iranian Kidney Transplant Recipients
(Başkent Üniversitesi, 2013-02) Azarpira, Negar; Ayatolahi, Maryam; Darai, Masumeh; Bahador, Ali; Geramizadeh, Bita; Aghdai, Mahdokht H.
Objectives: Nitric oxide is a major mediator in vascular biology and regulator of regional blood flow. Its production is catalyzed by the enzyme endothelial nitric oxide synthase. Protective actions of nitric oxide in ischemia and reperfusion are due to its potential as an antioxidant and anti-inflammatory agent, along with its inhibitory effects on cell signaling pathways of nuclear proteins, such as NF-κB. The endothelial nitric oxide synthase gene polymorphisms affect endothelial nitric oxide synthase activity and are associated with endothelial dysfunction. This study sought to examine the association between single nucleotide polymorphisms in endothelial nitric oxide synthase gene (rs 2070744, 27VNTR, and rs1799983) and the development of acute rejection in renal transplant patients. Materials and Methods: Sixty-six renal transplant recipients (33 patients with an episode of acute rejection and 33 recipients an episode of acute rejection), between June 2010 and March 2011, were included. The polymorphism was determined by simple polymerase chain reaction and polymerase chain reaction-restriction fragment-length polymorphism analysis. Results: There was only a significant association of endothelial nitric oxide synthase -786T allele and acute rejection (P = .03). Recessive model of T-786C alleles (TT vs TC+CC) and acute rejection confirmed a significant association (odds ratio: 3.12; 95% CI: 0.01-9.83; P = .025). Haplotype CbG was higher in recipients without rejection as compared to rejection group (OR: 0.42, 95% CI: 0.16-1.13; P < .05). Respecting the endothelial nitric oxide synthase gene 894G/T single nucleotide polymorphisms and 27VNTR, no significant association between the allele/genotype and acute rejection was seen. Conclusion: Recipient endothelial nitric oxide synthase gene polymorphisms do not alter the risk of acute rejection after a renal transplant. Rejection is a complex immunologic event. Therefore, finding associated genetic variants demands a multicentric larger sample size.
Interleukin-10 Gene Polymorphism in Bone Marrow Transplant Recipients
(Başkent Üniversitesi, 2008-03) Azarpira, Negar; Geramizadeh, Bita; Darai, Masumeh; Aghdaie, Mahdokht Hossein; Ramzi, Mani
Objectives: Graft-versus-host disease is the main complication after hematopoietic stem cell transplant, occurring even after donor and recipient human leukocyte antigen matching, apparently because of donor/recipient minor histocompatibility antigen mismatches and cytokine polymorphisms. Interleukin-10 suppresses several activities of the immune response by inhibiting T helper 1 and T helper 2 cells. These properties suggest that interleukin-10 could act as a suppressive mediator and prevent graft-versus-host disease. This study evaluates the association between the interleukin-10 promoter gene polymorphism and transplant outcomes among 18 recipients of cytokine-mobilized peripheral blood stem cells from human leukocyte antigen-matched sibling donors. Materials and Methods: We analyzed 3 single-nucleotide polymorphisms in the proximal region of the interleukin-10 promoter gene (-1082/-819/-592) by the amplification refractory mutation system and polymerase chain reaction-restriction fragment length polymorphism methods. Eighteen donors and their recipients who had undergone an allogeneic peripheral blood stem cell transplant at the Bone Marrow Transplant Center in Nemazi Hospital (Shiraz, Southern Iran) between September 2005 and September 2006 were enrolled. Results: The GCC haplotype (1082*G/819*C/592*C) was predominant in both the donor and the recipient, but no significant correlations were present between the GCC haplotype in either the donor or the recipient and the risk of acute graft-versus-host disease (P = .56). Conclusions: The interleukin-10 promoter gene polymorphism was found not to be associated with acute graft-versus-host disease in patients after an allogeneic peripheral blood stem cell transplant from human leukocyte antigen-matched sibling donors. Additional studies with larger samples are necessary to further define the influence of interleukin-10 on the immune response after bone marrow transplant.
Methylenetetrahydrofolate Reductase C677T Genotypes and Clinical Outcome Following Hematopoietic Cell Transplant
(Başkent Üniversitesi, 2007-12) Azarpira, Negar; Geramizadeh, Bita; Darai, Masumeh; Aghdaie, Mahdokht Hossein; Ramzi, Mani
Objective: Methotrexate may be used as a prophylactic agent against graft-versus-host disease in hematopoietic cell transplant. The drug exerts its effect on folate metabolism; 5,10-methylenetetrahydrofolate reductase is a critical enzyme involved in this cycle and is related to the toxicity of methotrexate. Methods: We examined the association of a single nucleotide polymorphism at position 677 in the 5,10-methylenetetrahydrofolate reductase gene and the clinical outcomes of patients treated with allogeneic hematopoietic cell transplant. Genotyping of 5,10-methylenetetrahydrofolate reductase was performed by polymerase chain reaction-restriction fragment length polymorphism on 30 patients receiving hematopoietic cell transplant and their HLA-matched related donors. Patients were given a short course of methotrexate as prophylaxis to prevent graft-versus-host disease. Results: Donors and recipients who carried a 677T allele showed mildly higher total bilirubin, aspartic transaminase, and alanine transaminase levels, but these increases above the normal values were not statistically significant (P > .05). The platelet recovery to 20 000/µL and granulocyte recovery to 500/µL were slower for patients who carried a 677T allele, but these correlations also were not statistically significant. The 5,10-methylenetetrahydrofolate reductase genotypes of neither the donors nor the recipients had any effect on the incidence of acute graft-versus-host disease. Conclusions: No association was observed between the C677T polymorphism and the outcome parameters for any of the different genotypes studied here. Additional studies with larger samples are necessary to further elucidate the influence of 5,10-methylenetetrahydrofolate reductase genotyping on clinical outcomes of patients treated with hematopoietic cell transplant who receive methotrexate.
Polymorphism of the Methylenetetrahydrofolate Reductase C677T Gene With Chronic Allograft Nephropathy in Renal Transplant Recipientsw
(Başkent Üniversitesi, 2008-03) Azarpira, Negar; Darai, Masumeh; Raisjalali, Ghanbar
Objectives: This study sought to investigate the frequency of the 5, 10-methylenetetrahydrofolate reductase gene (MTHFR C677T) in 127 patients (77 with chronic allograft nephropathy and 50 with normal renal function) who had undergone a renal transplant at least 20 months earlier to define the risk factors for chronic allograft dysfunction. Fifty healthy subjects served as controls. Materials and Methods: Genotypes were determined using polymerase chain reaction followed by restriction fragment length polymorphism analysis. The restriction enzyme for the MTHFR C677T variants was HinfI. Results: No statistically significant differences were seen between the allelic and genotypic distribution of the MTHFR polymorphism. Conclusions: Additional studies with larger sample sizes are needed to define the influence of MTHFR C677T genotyping on clinical outcomes in renal allograft recipients.
Thiopurine S-Methyltransferase Polymorphism in Iranian Kidney Transplant Recipients
(Başkent Üniversitesi, 2011-08) Aghdaie, Mahdokht Hossein; Malekhoseini, Seid Ali; Rahsaz, Marjan; Darai, Masumeh; Sagheb, Mehdi; Geramizadeh, Bita; Azarpira, Negar
Objectives: Thiopurine S-methyltransferase is an enzyme that catalyzes S-methylation of azathioprine as an immunosuppressive drug. Genetic polymorphisms influence thiopurine S-methyltransferase activity. There are 3 variant alleles: thiopurine S-methyltransferase*2, *3A, and *3C are responsible for more than 95% cases of low-enzyme activity. Materials and Methods: We studied these polymorphisms and the occurrence of azathioprine adverse effects in 50 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. Thiopurine S-methyltransferase genetic polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism assay and allele-specific polymerase chain reaction methods. Azathioprine dosage; leukocyte, erythrocyte, and platelet counts; and graft rejection episodes were analyzed during hospitalization. Results: Two patients (2%) were heterozygous for thiopurine S-methyltransferase*3C, the remaining patients were thiopurine S-methyltransferase wild-type *1/*1 (98%). Thiopurine S-methyltransferase wild-type homozygous and heterozygous patients were administered similar azathioprine dosages at the beginning of treatment (2.42 ± 0.50 and 2.52 ± 0.40 mg/kg/24 h). During subsequent days, mean azathioprine dosage administered to thiopurine S-methyltransferase wild-type homozygous patients was similar to heterozygous patients, but with no statistical difference (P = .28). Three patients had an acute rejection episode during this time. Five patients (10%) had reduced azathioprine dosage owing to adverse effects. Adverse reactions consisted of hematotoxicity (n=2), hepatotoxicity (n=1), and gastrointestinal toxicity (n=2). All recipients were wild-type homozygotes. Conclusions: The frequency of thiopurine S-methyltransferase gene mutations is low among our patients. The incidence of adverse reactions to azathioprine was also low, even in patients carrying a variant of thiopurine S-methyltransferase. We conclude that determining thiopurine S-methyltransferase genotype is not useful in our population to predict adverse reactions to azathioprine.