title: Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase).
abstract: Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
authors.affiliation: Purine Research Laboratory, Department of Chemical Pathology and Department of Gastroenterology, Guy's and St Thomas' Hospital, London, UK.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.forename: Azhar
authors.initials: A
authors.lastname: Ansari
authors.forename: John A
authors.initials: JA
authors.lastname: Duley
authors.forename: Monica
authors.initials: M
authors.lastname: Arenas
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sumi
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: El-Monsor
authors.initials: el-M
authors.lastname: Shobowale-Bakre
authors.forename: Emilia
authors.initials: E
authors.lastname: Escuredo
authors.forename: Lynette D
authors.initials: LD
authors.lastname: Fairbanks
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Sanderson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D002648:Child; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007293:Inosine Triphosphate / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D007166:Immunosuppressive Agents; D007293:Inosine Triphosphate; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase