[Show abstract][Hide abstract] ABSTRACT: Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Variability in TPMT activity is mainly due to genetic polymorphism. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) were determined in an Iranian population from south of Iran (n = 500), using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. Four hundred seventy four persons (94.8%) were homozygous for the wild type allele (TPMT*1/*1) and twenty five people were TPMT*1/*3C (5%). One patient was found to be heterozygous in terms TPMT*1 and *2 alleles with genotype of TPMT*1/*2 (0.2%). None of the participants had both defective alleles. The TPMT*3C and *2 were the only variant alleles observed in this population. The total frequency of variant alleles was 2.6% and the wild type allele frequency was 97.4%. The TPMT*3B and *3A alleles were not detected. Distributions of TPMT genotype and allele frequency in Iranian populations are different from the genetic profile found among Caucasian or Asian populations. Our findings also revealed inter-ethnic differences in TPMT frequencies between different parts of Iran. This view may help clinicians to choose an appropriate strategy for thiopurine drugs and reduce adverse drug reactions such as bone marrow suppression.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Transplantation of renal grafts is an established treatment for renal failure in a variety of medical conditions. Polymorphisms in genes, coding for proteins involved in immune response, may influence immunological and non-immunological mechanisms that lead to allograft loss. Vitamin D receptor (VDR) agonist has been shown to reduce short and long term allograft rejection in animal model. There are functional polymorphisms in VDR gene.
A total of 75 renal allograft recipients with at least 2 years follow-up were selected and genotyped for two polymorphisms in the VDR genes (FokI and BsmI) and the association of each genotype with renal allograft survival and acute rejection was evaluated.
We are unable to find statistically significant association between any of the study polymorphisms and clinical outcomes.
We have found no evidence to suggest that either VDR FokI or BsmI polymorphism determines the incidence of acute rejection or graft survival after renal transplantation. A larger sample size is necessary to confirm these findings.