title: Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression.
abstract: 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.
authors.affiliation: Laboratory of Experimental Internal Medicine, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. z.zelinkova@amc.uva.nl
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zelinkova
authors.forename: Luc J J
authors.initials: LJ
authors.lastname: Derijks
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Esther W M
authors.initials: EW
authors.lastname: Vogels
authors.forename: Antoine H C
authors.initials: AH
authors.lastname: van Kampen
authors.forename: Wouter L
authors.initials: WL
authors.lastname: Curvers
authors.forename: Danny
authors.initials: D
authors.lastname: Cohn
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: van Deventer
authors.forename: Daniël W
authors.initials: DW
authors.lastname: Hommes
mesh_terms: 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
chemical_list: D001379:Azathioprine; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase