Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipient

Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-met hyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with fou r prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G4 60A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transp lant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation -specific polymerase chain reaction-based methods) was observed in four pat ients (A719G: n=2; A719G plus G460: n=2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutat ion A719G and there was a 40% drop in neutrophils in the two other patients . Discontinuation of AZA in the four mutant patients corrected for the drop . Presence of TPMT mutations is associated with a greater likelihood of agr anulocytosis. Determination of these mutations could reduce the risk for he matological side-effects.