Original article
Inosine Triphosphate Pyrophosphatase and Thiopurine S-Methyltransferase Genotypes Relationship to Azathioprine-Induced Myelosuppression

https://doi.org/10.1016/j.cgh.2005.10.019Get rights and content

Background & Aims: The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients. Methods: ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn’s disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity. Results: Leukopenia (leukocyte count, <3.0 × 109/L) was observed in 4.6% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7% and 5.4%, respectively, for ITPA 94C>A, and 20.8% and 4%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95% confidence interval, 1.119–10.971 (P = .046); TPMT odds ratio, 6.316; 95% confidence interval, 2.141–18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity. Conclusions: ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.

Section snippets

Patient Selection

A retrospective cross-sectional study was performed by the Department of Gastroenterology and Hepatology of the Academic Medical Center, Amsterdam, the Netherlands. Medical records of all consecutive IBD patients who visited the IBD outpatient clinic from October 1995 until September 2003 were reviewed. Patients with a positive history of AZA use for whom reliable data on AZA use and related side effects could be obtained were eligible for the study. The indication and regimen of AZA treatment

Patients

A total of 262 IBD patients were included in this study. The mean AZA dose received in the whole patient population was 132 mg (range, 50–250 mg), with a mean duration of AZA exposure of 35 months (range, 1–143 mo). Patient characteristics are shown in Table 1.

Gene encoding inosine triphosphate pyrophosphatase and thiopurine S-methyltransferase allele frequencies

Allelic variants of ITPA and TPMT genes and their frequencies are shown in Table 2. Homozygosity for the ITPA 94C>A and IVS2+21A>C alleles has been found in 1 and 4 patients, respectively. Five patients were compound heterozygotes for

Discussion

We studied the allelic frequencies of earlier reported and clinically important polymorphisms of TPMT and ITPA, and their association with toxicity in IBD patients treated with AZA maintenance therapy. In this large cohort studied, we found that patients carrying TPMT (238G>C, 460G>A, and 719A>G) and ITPA (94C>A) allele mutations are at increased risk for developing leukopenia (TPMT odds ratio, 6.316; 95% CI, 2.141–18.634; P = .004; ITPA 94C>A odds ratio, 3.504; 95% CI, 1.119–10.971; P = .046).

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Z.Z. and L.J.J.D. contributed equally to this article.

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