title: Genetic Predictors of Azathioprine Toxicity and Clinical Response in Patients with Inflammatory Bowel Disease.
abstract: BACKGROUND
  Thiopurines (Azathioprine (AZA) and 6-Mercaptopurine (6-MP) are considered a well-established therapy for patients with Inflammatory Bowel Disease (IBD) including ulcerative colitis (UC) and Crohn's Disease (CD). However, nearly 20% of patients discontinue thiopurines due to adverse events. Functional polymorphisms of several enzymes involved in the metabolism of thiopurines have been linked with toxicity. The clinical value of variant carriers such as TPMT, ITPA and GSTs in predicting toxicity and adverse events for IBD patients treated with thiopurines remains to be clarified.
  
  
  OBJECTIVE
  To determine if variation in TPMT, ITPA and GST genotypes can predict adverse effects such as neutropenia, pancreatitis, liver enzyme elevation, as well as clinical response for patients with IBD treated with thiopurines.
  
  
  METHODS
  Patients known to have IBD and treated with AZA or 6MP were enrolled. Adverse effects were calculated and their correlation with TPMT, ITPA and GST genotypes was evaluated. Further, the correlation between clinical response and TPMT, ITPA and GST genotypes were assessed.
  
  
  RESULTS
  A total of 53 patients were enrolled. 16/53 patients (28.6%) responded to AZA therapy. 17 patients experienced adverse events with 10 having to discontinue treatment. Three patients (5.4%) developed severe myelosuppression (WBC< 2.0 or neutrophils <1.0). Loss of function TPMT genotype was associated with adverse events (OR 3.64, 95% CI 0.55 - 24.23, p=0.0313). ITPA and GST polymorphisms were not associated with toxicity. GSTM1 deletion was associated with poor clinical response to therapy (OR 3.75, 95% CI 0.940 - 14.97, p=0.1028), however, neither TPMT*3A nor ITPA polymorphisms were associated with clinical response.
  
  
  CONCLUSIONS
  In addition to TPMT for adverse events, genotyping for GSTM1 appears to predict clinical response in IBD patients treated with thiopurines.
authors.forename: B
authors.initials: B
authors.lastname: Al-Judaibi
authors.forename: U I
authors.initials: UI
authors.lastname: Schwarz
authors.forename: N
authors.initials: N
authors.lastname: Huda
authors.forename: G K
authors.initials: GK
authors.lastname: Dresser
authors.forename: J C
authors.initials: JC
authors.lastname: Gregor
authors.forename: T
authors.initials: T
authors.lastname: Ponich
authors.forename: N
authors.initials: N
authors.lastname: Chande
authors.forename: M
authors.initials: M
authors.lastname: Mosli
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001379:Azathioprine; D005819:Genetic Markers; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents