Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease
Article first published online: 3 JUN 2009
© 2009 Blackwell Publishing Ltd
Alimentary Pharmacology & Therapeutics
Volume 30, Issue 4, pages 375–384, August 2009
How to Cite
SMITH, M. A., MARINAKI, A. M., ARENAS, M., SHOBOWALE-BAKRE, M., LEWIS, C. M., ANSARI, A., DULEY, J. and SANDERSON, J. D. (2009), Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Alimentary Pharmacology & Therapeutics, 30: 375–384. doi: 10.1111/j.1365-2036.2009.04057.x
- Issue published online: 20 JUL 2009
- Article first published online: 3 JUN 2009
- Publication data Submitted 6 May 2009 First decision 13 May 2009 Resubmitted 2 June 2009 Accepted 2 June 2009 Epub Accepted Article 3 June 2009
Background Azathioprine (AZA) pharmacogenetics are complex and much studied. Genetic polymorphism in TPMT is known to influence treatment outcome. Xanthine oxidase/dehydrogenase (XDH) and aldehyde oxidase (AO) compete with TPMT to inactivate AZA.
Aim To assess whether genetic polymorphism in AOX1, XDH and MOCOS (the product of which activates the essential cofactor for AO and XDH) is associated with AZA treatment outcome in IBD.
Methods Real-time PCR was conducted for a panel of single nucleotide polymorphism (SNPs) in AOX1, XDH and MOCOS using TaqMan SNP genotyping assays in a prospective cohort of 192 patients receiving AZA for IBD.
Results Single nucleotide polymorphism AOX1 c.3404A > G (Asn1135Ser, rs55754655) predicted lack of AZA response (P = 0.035, OR 2.54, 95%CI 1.06–6.13) and when combined with TPMT activity, this information allowed stratification of a patient’s chance of AZA response, ranging from 86% in patients where both markers were favourable to 33% where they were unfavourable (P < 0.0001). We also demonstrated a weak protective effect against adverse drug reactions (ADRs) from SNPs XDH c.837C > T (P = 0.048, OR 0.23, 95% CI 0.05–1.05) and MOCOS c.2107A > C, (P = 0.058 in recessive model, OR 0.64, 95%CI 0.36–1.15), which was stronger where they coincided (P = 0.019).
Conclusion These findings have important implications for clinical practice and our understanding of AZA metabolism.