Başkent Üniversitesi Yayınları
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Item 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, NegarObjectives: 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.Item 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, ManiObjective: 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.