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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.

Original publication

DOI

10.1007/s00147-004-0737-0

Type

Journal article

Journal

Transpl Int

Publication Date

10/2004

Volume

17

Pages

531 - 539

Keywords

Azathioprine, Dose-Response Relationship, Drug, Gene Frequency, Genotype, Humans, Immunosuppressive Agents, Kidney Transplantation, Leukopenia, Methyltransferases, Polymorphism, Genetic, Promoter Regions, Genetic, Retrospective Studies, Tandem Repeat Sequences, Time Factors