Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression.
OBJECTIVE
The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients.


METHODS
ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn's disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity.


RESULTS
Leukopenia (leukocyte count, <3.0 x 10(9)/L) was observed in 4.6% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7% and 5.4%, respectively, for ITPA 94C>A, and 20.8% and 4%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95% confidence interval, 1.119-10.971 (P = .046); TPMT odds ratio, 6.316; 95% confidence interval, 2.141-18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity.


CONCLUSIONS
ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.
Zelinkova
Zuzana
Z
Laboratory of Experimental Internal Medicine, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. z.zelinkova@amc.uva.nl
Derijks
Luc J J
LJ
Stokkers
Pieter C F
PC
Vogels
Esther W M
EW
van Kampen
Antoine H C
AH
Curvers
Wouter L
WL
Cohn
Danny
D
van Deventer
Sander J H
SJ
Hommes
Daniël W
DW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D000097630:Inosine Triphosphatase
D001379:Azathioprine; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase