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 ofTPMTgenotyping 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 theTPMT alleles*2, *3A, *3B and *3C in 108 thiopurinetreated 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 variantTPMT*3B/*3C. The overall concordance rate betweenTPMTgenotypes 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.
Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, (Maria Gazouli, Nicholas P. Anagnou).
Muaria
M
Gazouli
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
Ioanna
I
Pachoula
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
Ioanna
I
Panayotou
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
Georgios
G
Chouliaras
Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, (Maria Gazouli, Nicholas P. Anagnou) ; Laboratory of Cell and Gene Therapy, Centre of Basic Research II, Foundation for Biomedical Research of the Academy of Athens (IIBEAA) (Nicholas P. Anagnou), Athens, Greece.
Nicholas P
NP
Anagnou
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
George
G
Chroussos
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
Eleftheria
E
Roma
6MP; TPMT; azathioprine; inflammatory bowel disease; pharmacogenetics