engleski

Inosine triphosphate pyrophosphatase and xanthine oxidase gene variability in Croatian inflammatory bowel disease patients

Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice azathioprine (AZA) or 6- mercaptopurine (6-MP) are not effective in one- third of patients and up to one-fifth of patients discontinue thiopurine therapy due to adverse reactions. The observed interindividual differences in therapeutic response and toxicity to thiopurines are explained to a large extent by the variable formation of active metabolites, which is at least partly caused by genetic polymorphisms of the genes encoding crucial enzymes in thiopurine metabolism. Among them, of recognized importance are thiopurine S- methyltransferase (TPMT), xanthine oxidase (XO) and inosine triphosphate pyrophosphatase (ITPA). While genetic variability in TPMT has been translated into practical guidelines the importance of XO and ITPA is not still fully understood. ITPA catalyzes the pyrophosphohydrolysis of inosine triphosphate (6- TITP) to inosine monophosphate (6-TIMP), thereby preventing an abnormal accumulation of 6-TITP nucleotides in cells and their incorporation into RNA and DNA. ITPA deficiency has been related with non-myelosuppression adverse effects such as pancreatitis, nausea, flu-like symptoms and skin rashes in patients treated with AZA/6-MP. XO catalyzes the catabolism of 6-MP to 6-thiouric acid. 6-MP induced adverse effects may increase in poor XO metabolizers. Since genetic variability shows marked interindividual and interethnic differences, the aim of this study was to examine the allelic variations of of ITPA and XO in Croatian IBD patients. PATIENTS and METHODS. DNA of 235 patients with IBD was genotyped for ITPA 94C>T, ITPA124+21A>C, XO 837C>T, XO 2211C>T by methods based on RealTime Polymerase Chain Reaction. RESULTS. Concerning the 94C>A variant of the ITPA gene, 198 (86.1%) individuals were homozygous for the wild-type allele (C/C), 30(13%) were heterozygous (A/C), and 2 (0.9%) were homozygous for the mutant allele (A/A). For ITPA 124+21A>C, 143 (60.8%) individuals were homozygous for the wild-type (A/A), 89 (37.9%) were heterozygous (A/C) and 3(1.3%) were homozygous for the mutated allele (C/C). Concerning the 837C>T variant of the XO gene, 203 (90.2%) individuals were homozygous for the wild- type allele (C/C) and 22(9.8%) were heterozygous (A/C). For XO 2211C>T 98 (43.6%) individuals were homozygous for the wild-type (C/C), 89 (42.6%) were heterozygous (C /T) and 31(13.8%) were homozygous for the mutated allele (T/T). CONCLUSION. ITPA and XO exhibit considerable variability in Croatian population which could be, besides TPMT polymorphism, additional risk factors for thiopurine drug adverse reactions.

inflammatory bowel disease (IBD); thiopurines; thiopurine S-methyltransferase (TPMT); xanthine oxidase (XO); inosine triphosphate pyrophosphatase (ITPA); genetic polymorphisms

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