Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease.
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.


OBJECTIVE
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).


CONCLUSIONS
These findings have important implications for clinical practice and our understanding of AZA metabolism.
Smith
M A
MA
Department of Gastroenterology, Guy's & St. Thomas' NHS Foundation Trust, London, UK.
Marinaki
A M
AM
Arenas
M
M
Shobowale-Bakre
M
M
Lewis
C M
CM
Ansari
A
A
Duley
J
J
Sanderson
J D
JD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D042931:Aldehyde Oxidase / Q000235:genetics* / Q000378:metabolism; D001379:Azathioprine / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D013223:Statistics as Topic; D016896:Treatment Outcome; D014968:Xanthine Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D007166:Immunosuppressive Agents; D000429:Alcohol Oxidoreductases; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D042931:Aldehyde Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine