IMPDH1 promoter mutations in a patient exhibiting azathioprine resistance.
Around 9% of inflammatory bowel disease (IBD) patients are resistant to azathioprine. We hypothesized that these patients may carry mutations within inosine-5'-monophosphate dehydrogenase (IMPDH). To test this hypothesis, we screened 20 azathioprine-resistant patients for variations in the two IMPDH genes (IMPDH1 and IMPDH2) using dHPLC and DNA sequencing. A 9 bp insertion within the IMPDH1 P3 promoter was found in a patient exhibiting severe azathioprine resistance. The insertion is predicted to abolish a cAMP-response element (CRE) and was found to significantly reduce IMPDH1 P3 promoter activity in a luciferase reporter gene assay (P-value <0.001). This in vitro assay suggests the variant promoter has altered function in vivo and consequently may have contributed to the thiopurine resistance observed in this patient. The absence of functional variants within the other patients indicates that if IMPDH genetic variability contributes to azathioprine resistance it does so infrequently.
Roberts
R L
RL
Department of Pathology, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand. rebecca.roberts@chmeds.ac.nz
Gearry
R B
RB
Barclay
M L
ML
Kennedy
M A
MA
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use*; D001483:Base Sequence; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D005787:Gene Frequency; D017930:Genes, Reporter; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D049409:Luciferases, Firefly / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D014162:Transfection
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human; D049409:Luciferases, Firefly; D001379:Azathioprine