P228. Thiopurine methyltransferase genotype and thiopurine S‑methyltransferase activity in Greek children with inflammatory bowel disease
M. Gazouli1, I. Pachoula2, I. Panayotou2, G. Chouliaras2, N. Anagnou1, E. Roma2
1School of Medicine, University of Athens, Greece; 2First Department of Pediatrics, Aghia Sophia Children's Hospital, School of Medicine, University of Athens, Greece, Greece
Background: Azathioprine (AZA) and 6‑mercaptopurine (6MP) are used in the treatment of paediatric 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 activity was measured and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C in 108 thiopurine-treated paediatric IBD patients (44.44% boys and 55.56% girls) with a mean age 11.3 years (range 316).
Results: TPMT activity levels in our whole population ranged from 0.36 up to 78 U/gHb. Significant TPMT activity differences between wild-type and heterozygous and homozygous mutated subjects were observed. We divided our TPMT activity into three categories according to our frequency distribution: low (16.67%), intermediate (25.92%) and high (57.41%), with arbitrary cut-off values of 5.5, 15.5 and >15.6 U/gHb, respectively. The whole population had 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 of carriers of at least one variant allele and with low or intermediate TPMT activity developed adverse effects.
Conclusions: Our findings suggest that carriers of at least one variant allele and with both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and TPMT activity.