TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment

Abstract

BACKGROUND: Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Patients with intermediate or deficient TPMT activity are at risk of toxicity after receiving standard doses of these drugs. OBJECTIVE: This study determined the frequencies of TPMT alleles (TPMT*2, *3A, *3B and *3C) and explored the association between TPMT genetic polymorphism and the development of adverse drug reactions in Chinese renal transplant patients receiving azathioprine (AZA). METHODS: TPMT genotypes were determined using polymerase chain reaction-based assays in 122 renal transplant patients and 210 healthy subjects. Biochemical and clinical data were retrospectively evaluated after renal transplantation. RESULTS: Of 122 patients, eight (allele frequency 3.28%) were heterozygous for TPMT*3C and no TPMT*2, *3A or *3B or homozygous TPMT*3C subjects were identified. The pattern and frequency of the main mutant TPMT alleles were similar in patients and healthy subjects. Four of five patients (80%) with haematopoietic toxicity were heterozygotes. TPMT heterozygosity was associated with significant reductions in haematological indices and a significant decrease in cyclosporine plasma concentrations in the first year after renal transplantation. No association between TPMT genotype and renal rejection was identified. CONCLUSION: Our results, together with those of others pointing in the same direction, suggest that genotyping the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.