title: Thiopurine S-methyltransferase polymorphism in Iranian kidney transplant recipients.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Organ Transplant Research Center, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Mahdokht Hossein
authors.initials: MH
authors.lastname: Aghdaie
authors.forename: Negar
authors.initials: N
authors.lastname: Azarpira
authors.forename: Bita
authors.initials: B
authors.lastname: Geramizadeh
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sagheb
authors.forename: Masumeh
authors.initials: M
authors.lastname: Darai
authors.forename: Marjan
authors.initials: M
authors.lastname: Rahsaz
authors.forename: Seid Ali
authors.initials: SA
authors.lastname: Malekhoseini
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000517:prevention & control*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D007492:Iran; D016030:Kidney Transplantation; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine