Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease

Aliment Pharmacol Ther. 2008 Oct 15;28(8):973-83. doi: 10.1111/j.1365-2036.2008.03788.x.


Aim: 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Azathioprine / adverse effects*
  • Genotype
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / genetics
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Middle Aged
  • Predictive Value of Tests
  • Prospective Studies
  • Thionucleotides / genetics
  • Thionucleotides / metabolism*
  • Young Adult


  • Immunosuppressive Agents
  • Thionucleotides
  • Methyltransferases
  • thiopurine methyltransferase
  • Azathioprine