Thiopurine methyltransferase genotype and thiopurine S-methyltransferase activity in Greek children with inflammatory bowel disease

Background Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of pediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to examine the sensitivity and specificity of TPMT genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in children with IBD. Methods TPMT red blood cell (RBC) activity was measured by using a radiochemical method and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C in 108 thiopurine-treated pediatric IBD patients with a mean age of 11.3 years (range 3-16). Results Significant TPMT activity differences between wild-type and heterozygous and homozygous mutated subjects were observed. We divided TPMT activity into three categories according to frequency distribution: low (16.67%), intermediate (25.92%) and high (57.41%). The whole population included a total of 77.78% of homozygous wild-type subjects, 15.74% heterozygous variants, 1.85% homozygous variants and five (4.63%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 88.2%. Seven carriers of at least one variant allele and low or intermediate TPMT activity developed adverse effects. Conclusions Our findings suggest that carriers of at least one variant allele and both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and TPMT activity.