The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation

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 greater than or equal to 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.