Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines' toxicity and efficacy.

Abstract

AIM:

To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn's disease and ulcerative colitis.

METHODS:

In 422 consecutive patients (250 with Crohn's disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy.

RESULTS:

Seventy-three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) (P < 0.001); no correlation with other ADRs and efficacy of therapy was found. Conversely, the frequency of inosine triphosphate pyrophosphatase and HPRT1 risk genotypes was not significantly different in patients with ADRs (included leucopenia). Non-responders had an increased frequency of inosine triphosphate pyrophosphatase risk genotypes (P = 0.03).

CONCLUSIONS:

The majority of azathioprine/mercaptopurine-induced ADRs and efficacy of therapy are not explained by the investigated gene polymorphisms. The combined evaluation of all three genes enhanced the correlation with leucopenia (43.5% vs. 23% in controls) (P = 0.008), at the expense of a reduced accuracy (60%).

• Authors: O Palmieri, A Latiano, F Bossa, M Vecchi, R D'Incà, D Guagnozzi, F Tonelli, S Cucchiara, M R Valvano, T Latiano, A Andriulli, V Annese
• Journal: Alimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 26 Issue 5 Pg. 737-45 (Sep 01 2007) ISSN: 0269-2813 [Print] England
• PMID: 17697207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gastrointestinal Agents
• Methyltransferases
• Pyrophosphatases

Topics

• Adult
• Female
• Gastrointestinal Agents (administration & dosage, adverse effects, pharmacokinetics)
• Genotype
• Humans
• Inflammatory Bowel Diseases (drug therapy)
• Leukopenia (chemically induced)
• Male
• Methyltransferases (adverse effects, metabolism)
• Middle Aged
• Polymorphism, Genetic
• Pyrophosphatases (adverse effects)
• Treatment Outcome
• Inosine Triphosphatase