Introduction Multidrug resistance (MDR) genes encode transmembrane ATP-dependent pumps, otherwise known as the ATP-binding cassette subfamily-b (ABCB) transporters responsible for removing xenobiotics, particularly drugs, from cells. Thiopurine metabolites are exported from cells by MDR-4 and MDR-5. Altered ABCB pump activity has been linked to treatment resistance in other contexts.
Methods Using Taqman® real-time PCR genotyping assays, a prospective cohort of 192 patients receiving azathioprine for IBD was genotyped for three coding region SNPs in MDR4 and three in MDR5, (all of which occur commonly in the Caucasian population). The SNPs tested were in MDR4: 175C→T, 711A→T and 1954A→G and in MDR5: 2T→C, 343A→G and 1573G→A. Association between genotype and clinical outcome on azathioprine treatment (complete response, non-response or withdrawal due to side-effects) was sought. Association tests were performed under a dominant model, using Fisher's Exact test. No correction for multiple testing has been applied.
Results The SNP MDR-5 c.343A→G was associated with a lack of clinical response to thiopurine treatment p=0.02, OR 2.43, 95%CI 1.14 to 5.17. Moreover, when analysed alongside other known markers of non-response to thiopurine treatment, (TPMT activity >35 pmol/h/mgHb and AOX 3404A→G) increasing numbers of markers increased their chance of non-response, p=0.0001 (χ2 for trend). No other SNP had a significant effect on clinical response and no SNP was associated with ADRs.
Conclusion This study raises the possibility that MDR polymorphism could be important in thiopurine pharmacogenetics and warrants further study in other cohorts. Reliable markers of non-response to thiopurines could be incorporated into a panel of pharmacogenetic markers to inform the selection and dosing of immunomodulatory drugs, offering each individual the best chance of achieving early effective disease control Abstract 043.
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