title: The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation.
abstract: Azathioprine metabolism is influenced by activity of the enzyme thiopurine S-methyltransferase (TPMT), which varies markedly between individuals. In this study we examined the influence of TPMT gene polymorphisms on azathioprine dose 1 year after renal transplantation. TPMT coding and promoter genotypes were determined using PCR-based assays. Azathioprine dose, white cell count, and intercurrent events throughout the first year after renal transplantation were ascertained from contemporaneous clinical notes. All patients analysed ( n=172) received an initial azathioprine dose of 1.5 mg/kg per day. Twelve individuals with one variant TPMT coding allele were detected (*3A n=11, *3C n=1). Of these, 58% required azathioprine dose reduction because of leucopenia, compared to only 30% of homozygous wild-type patients ( P=0.04). A significant correlation between the presence of >/=11 variable number tandem repeats (VNTRs) in the TPMT promoter and reduction in azathioprine dose was also identified ( P=0.001). We concluded that when azathioprine is administered at an initial dose of 1.5 mg/kg per day, both coding and promoter TPMT polymorphisms influence the dose tolerated.
authors.affiliation: Oxford Transplant Centre and Nuffield Department of Surgery, Oxford Radcliffe Hospitals, Oxford, UK.
authors.forename: Margarete A
authors.initials: MA
authors.lastname: Fabre
authors.forename: Des C
authors.initials: DC
authors.lastname: Jones
authors.forename: Mike
authors.initials: M
authors.lastname: Bunce
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morris
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Friend
authors.forename: Ken I
authors.initials: KI
authors.lastname: Welsh
authors.forename: Sara E
authors.initials: SE
authors.lastname: Marshall
mesh_terms: D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced; D008780:Methyltransferases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D020080:Tandem Repeat Sequences; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine