Abstract
Azathioprine (AZA) and mercaptopurine (MP – also known as 6-mercaptopurine or 6MP) are the first line immunomodulatory treatments for inflammatory bowel disease (IBD) with proven efficacy for multiple clinical outcomes (fistula closure, steroid withdrawal, maintenance of remission etc.). They also have a wide application in the fields of rheumatology, dermatology, haematology and transplant medicine. However these drugs also cause toxicity and may be ineffective. Both of these outcomes can have serious consequences for the individual concerned. A proportion of toxicity caused by these drugs is explained by genetic polymorphism in the enzyme thiopurine methyltransferase (TPMT), however the majority of toxicity remains unexplained and as yet there is no satisfactory explanation for the variable efficacy of these drugs.In this thesis I explore the impact of genetic polymorphism in several novel candidate genes involved in thiopurine metabolism on the success of thiopurine treatment. Single nucleotide polymorphisms (SNPs) in xanthine oxidase/dehydrogenase (XDH) and the final enzymatic step which activates its essential cofactor (molybdenum cofactor sulfurase, MOCOS) are shown to protect against side effects to AZA therapy. Polymorphism in aldehyde oxidase (AOX) and multi-drug resistance protein 5 on the other hand, are shown to predict a lack of response to thiopurine treatment. Sequencing AOX validated the real-time PCR results and suggested that there were no other coding SNPs likely to be contributory. A pharmacogenetic index incorporating these new markers with established predictors of outcome on thiopurines is presented and the clinical utility of such an index discussed. Finally, clinical data supporting the optimisation of azathioprine therapy, both by the measurement of thioguanine metabolite profiles and through co-prescription of allopurinol are presented.
| Date of Award | 2016 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jeremy Sanderson (Supervisor) & Anthony Marinaki (Supervisor) |