TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients.
OBJECTIVE
Thiopurine drugs have to be withdrawn in 10-30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines' metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor.


METHODS
The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles.


RESULTS
Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 x 10(9)/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk.


CONCLUSIONS
Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.
Kurzawski
Mateusz
M
Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, Szczecin 70-111, Poland. mkurz@op.pl
Dziewanowski
Krzysztof
K
Lener
Agnieszka
A
Drozdzik
Marek
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011044:Poland; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D055815:Young Adult; D000097630:Inosine Triphosphatase
D001379:Azathioprine; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase