title: Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease.
abstract: OBJECTIVE
  To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.
  
  
  METHODS
  Patients with IBD were given 2 mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6 months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.
  
  
  RESULTS
  Two hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P < 0.001). The ITPA 94C>A mutation was associated with withdrawal due to flu-like symptoms (P = 0.014). A baseline TPMT activity below 35 pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35 pmo/h/mg/Hb (81% vs. 43% respectively, P < 0.001). Patients achieving a mean TGN level above 100 were significantly more likely to respond (P = 0.0017).
  
  
  CONCLUSIONS
  TPMT testing predicts adverse effects and reduced chance of clinical response (TPMT >35 pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response.
authors.affiliation: Department of Gastroenterology, St Thomas' Hospitals Foundation, NHS Trust, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ansari
authors.forename: M
authors.initials: M
authors.lastname: Arenas
authors.forename: S M
authors.initials: SM
authors.lastname: Greenfield
authors.forename: D
authors.initials: D
authors.lastname: Morris
authors.forename: J
authors.initials: J
authors.lastname: Lindsay
authors.forename: K
authors.initials: K
authors.lastname: Gilshenan
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Lewis
authors.forename: A
authors.initials: A
authors.lastname: Marinaki
authors.forename: J
authors.initials: J
authors.lastname: Duley
authors.forename: J
authors.initials: J
authors.lastname: Sanderson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D013873:Thionucleotides; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine