Allele Frequency of Inosine Triphosphate Pyrophosphatase Gene Polymorphisms in a Japanese Population

Marinaki, A.; Sumi, Satoshi; Arenas, Monica; Fairbanks, Lynette D.; Harihara, Shinji; Shimizu, Kazuhiro; Ueta, Akihito; Duley, JA

doi:10.1081/ncn-200027641

Cited by 19 publications

(12 citation statements)

References 2 publications

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“…With respect to ITPA, the allele frequency of the ITPA 94C4A mutation in Korean IBD patients was 0.140, higher than that found in Europeans (0.060-0.070) and similar to the frequencies found in Japanese (0.135) and Chinese (0.15) populations. 17,18 Nevertheless, we did not find any evidence of an association between the ITPA genotype and clinical outcomes. Further research is warranted to reveal the true impact of TPMT/ITPA on the clinical efficacy of thiopurines.…”

Section: Discussioncontrasting

confidence: 52%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P¼0.903) or ITPA (P¼0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy. Keywords: azathioprine; inflammatory bowel disease; inosine triphosphate pyrophosphatase; relapse; thiopurine S-methyl transferase INTRODUCTION Thiopurine drugs, 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA), are effective for the induction and maintenance of remission in patients with inflammatory bowel disease (IBD). 1,2 There has been tremendous interest with regard to thiopurine metabolism as a means of identifying ways in which individual therapy might maximize clinical response and minimize adverse effects. Genetic polymorphisms in the thiopurine S-methyl transferase (TPMT) gene have been associated with decreased TPMT activity and the development of myelotoxicity due to high thioguanine metabolite concentrations. 3,4 Moreover, inosine triphosphate pyrophosphatase (ITPA) deficiency has recently been associated with AZA toxicity because of the accumulation of 6-thioinosine-triphosphate. 5,6 Theoretically, low TPMT activity might also augment the therapeutic efficacy of thiopurines and lead to better long-term clinical outcomes. To confirm the usefulness of the TPMT/ITPA genotype or TPMT activity in clinical prediction, research regarding the relevance of measurement for prevention of both adverse effects and clinical outcomes is necessary. However, the impact of the TPMT/ITPA genotype on long-term clinical response of IBD patients treated with AZA/6-MP has not yet been examined. In this study, we investigated whether TPMT/ ITPA genotypes could affect long-term clinical outcomes as measured by disease relapse in Korean patients with IBD undergoing AZA or 6-MP treatment. MATERIALS AND METHODSA total of 204 patients with IBD (105 patients with Crohn's disease, 59 with ulcerative colitis and 40 with intestinal Behcet's disease) were initiated on AZA treatment during the s...

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Section: Discussioncontrasting

confidence: 52%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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“…Implication of the ITPA Deficiency Mutant P32T: Cross-talk between Monomers-The observation that individuals heterozygous for the P32T mutation retained 25% ITPase activity (9) suggested that both protomers of the physiological dimer need to be intact for catalytic activity. The ITPA dimer structure presented here suggests an allosteric regulatory mechanism by cross-talk between the protomers.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of Human Inosine Triphosphatase

Stenmark

Kursula

Flodin

et al. 2007

Journal of Biological Chemistry

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Inosine triphosphatase (ITPA) is a ubiquitous key regulator of cellular non-canonical nucleotide levels. It breaks down inosine and xanthine nucleotides generated by deamination of purine bases. Its enzymatic action prevents accumulation of ITP and reduces the risk of incorporation of potentially mutagenic inosine nucleotides into nucleic acids. Here we describe the crystal structure of human ITPA in complex with its prime substrate ITP, as well as the apoenzyme at 2.8 and 1.1 Å , respectively. These structures show for the first time the site of substrate and Mg 2؉ coordination as well as the conformational changes accompanying substrate binding in this class of enzymes. Enzyme substrate interactions induce an extensive closure of the nucleotide binding grove, resulting in tight interactions with the base that explain the high substrate specificity of ITPA for inosine and xanthine over the canonical nucleotides. One of the dimer contact sites is made up by a loop that is involved in coordinating the metal ion in the active site. We predict that the ITPA deficiency mutation P32T leads to a shift of this loop that results in a disturbed affinity for nucleotides and/or a reduced catalytic activity in both monomers of the physiological dimer.

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“…The ITPA gene is orthologous to microbial genes Mj0226 , rdgB and HAM1 . Several allelic variants of the ITPA gene have been described in different human populations: the coding sequence ITPA 94C->A causing a P32T change in the corresponding protein and changes in introns, ITPA IVS2 + 21A->C, and most recently found ITPA IVS2 + 68T->C and ITPA IVS2 + 68T->G alleles 29; 30; 31; 32; 33; 34; 35. All of these variants are associated with different ranges of decreased ITPase activity.…”

Section: Introductionmentioning

confidence: 99%

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

Stepchenkova

Tarakhovskaya

Spitler

et al. 2009

Journal of Molecular Biology

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Sanitization of the cellular nucleotide pools from mutagenic base analogs is necessary for the accuracy of transcription and replication of genetic material and plays a substantial role in cancer prevention. The undesirable mutagenic, recombinogenic and toxic incorporation of purine base analogs (i.e. ITP, dITP, XTP, dXTP or 6-hydroxyaminopurine (HAP) deoxynucleoside triphosphate) into nucleic acids is prevented by inosine triphosphate pyrophosphatase (ITPA). The ITPA gene is a highly conserved, moderately expressed gene. Defects in ITPA orthologs in model organisms cause severe sensitivity to HAP and chromosome fragmentation. A human polymorphic allele 94C->A encodes for the enzyme with a P32T amino acid change and leads to accumulation of non-hydrolyzed ITP. ITPase activity is not detected in erythrocytes of these patients. The P32T polymorphism has also been associated with adverse sensitivity to purine base analog drugs. We have found that the ITPA-P32T mutant is a dimer in solution, as is wild-type ITPA, and has normal ITPA activity in vitro, but the melting point of ITPA-P32T is 5 degrees C lower than that of wild-type. ITPA-P32T is also fully functional in vivo in model organisms as determined by a HAP mutagenesis assay and its complementation of a bacterial ITPA defect. The amount of ITPA protein detected by western blot is severely diminished in a human fibroblast cell line with the 94C->A change. We propose that the P32T mutation exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability and availability.

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Allele Frequency of Inosine Triphosphate Pyrophosphatase Gene Polymorphisms in a Japanese Population

Cited by 19 publications

References 2 publications

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Crystal Structure of Human Inosine Triphosphatase

Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

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