Pharmacogenetics of thiopurine therapy in paediatric IBD patients.
BACKGROUND
Azathioprine is widely used in the treatment of children with inflammatory bowel disease. The occurrence and type of adverse events to azathioprine may be related to thiopurine S-methyltransferase (TPMT) enzyme activity and to inosine triphophate pyrophosphatase (ITPase) deficiency.


OBJECTIVE
Investigate frequencies of functional TPMT polymorphisms and ITPA polymorphisms and their association with the occurrence of adverse events during azathioprine therapy in a paediatric inflammatory bowel disease population.


METHODS
Seventy-two azathioprine treated paediatric inflammatory bowel disease patients, 47% girls, mean age 12.5 years (range 6.5-17.5), were assessed for TPMT and ITPA polymorphisms and for adverse events. The relation between polymorphisms and adverse events is evaluated.


RESULTS
Of all azathioprine treated patients, 11 experienced an adverse event for which azathioprine was stopped: pancreatitis (n = 4), leucopenia (n = 2) and 'general malaise' (n = 5). Of the 11 patients who stopped azathioprine because of adverse events, 10 had wild-type alleles for all investigated genotypes. Genotyping of ITPA 94C>A polymorphisms showed that two patients were homozygous, both tolerated azathioprine well.


CONCLUSIONS
No association of functional ITPA and TPMT polymorphisms and the occurrence of azathioprine related adverse events could be detected. Pharmacogenetic assessment prior to thiopurine therapy does not seem warranted.
De Ridder
L
L
Department of Paediatric Gastroenterology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands. l.deridder@amc.uva.nl
Van Dieren
J M
JM
Van Deventer
H J H
HJ
Stokkers
P C F
PC
Van der Woude
J C J
JC
Van Vuuren
A J
AJ
Benninga
M A
MA
Escher
J C
JC
Hommes
D W
DW
D000293:Adolescent; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D016009:Chi-Square Distribution; D002648:Child; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D010195:Pancreatitis / Q000139:chemically induced; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
D001379:Azathioprine; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase