Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase)

Marinaki, AM, Ansari, A, Duley, JA, Arenas, M, Sumi, S, Lewis, CM, Shobowale-Bakre, EM, Escuredo, E, Fairbanks, LD and Sanderson, JD (2004) Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics, 14 3: 181-187.


Author Marinaki, AM
Ansari, A
Duley, JA
Arenas, M
Sumi, S
Lewis, CM
Shobowale-Bakre, EM
Escuredo, E
Fairbanks, LD
Sanderson, JD
Title Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase)
Journal name Pharmacogenetics   Check publisher's open access policy
ISSN 0960-314X
Publication date 2004
Sub-type Article (original research)
DOI 10.1097/01.fpc0000114709.42625.5d
Volume 14
Issue 3
Start page 181
End page 187
Total pages 7
Place of publication Philadelphia
Publisher Lippincott Williams & Wilkins
Language eng
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. (C) 2004 Lippincott Williams Wilkins.
Keyword Biotechnology & Applied Microbiology
Genetics & Heredity
Pharmacology & Pharmacy
azathioprine
6-mercaptopurine
ITPA
ITPase
inosine triphosphate pyrophosphatase
thiopurine methyltransferase
side-effects
inflammatory bowel disease
Thiopurine S-methyltransferase
Inflammatory-bowel-disease
Pyrophosphohydrolase Deficiency
6-mercaptopurine Therapy
Catalytic Activity
Crohns-disease
Pharmacogenetics
Intolerance
Leukemia
Mutation
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Pharmacy Publications
 
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