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Raghunadharao Digumarti - One of the best experts on this subject based on the ideXlab platform.

Sung Pil Hong - One of the best experts on this subject based on the ideXlab platform.

Anthony M. Marinaki - One of the best experts on this subject based on the ideXlab platform.

  • Inosine Triphosphate Pyrophosphohydrolase (ITPA) polymorphic sequence variants in adult hematological malignancy patients and possible association with mitochondrial DNA defects
    Journal of hematology & oncology, 2013
    Co-Authors: Mazin A. Zamzami, Anthony M. Marinaki, John A. Duley, Gareth Price, Deon J. Venter, John W. Yarham, Robert W. Taylor, L. Catley, Timothy H. Florin, Francis Bowling
    Abstract:

    Background Inosine Triphosphate pyrophosphohydrolase (ITPase) is a ‘house-cleaning’ enzyme that degrades non-canonical (‘rogue’) nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects. Furthermore, we investigated whether accumulating mtDNA defects may then be a risk factor for cell transformation, in adult haematological malignancy (AHM).

  • The ITPA c.94C > A and g.IVS2 + 21A > C sequence variants contribute to missplicing of the ITPA gene
    Biochimica et biophysica acta, 2006
    Co-Authors: M. Arenas, John A. Duley, Satoshi Sumi, Jeremy D Sanderson, Anthony M. Marinaki
    Abstract:

    Inosine Triphosphate pyrophosphatase (ITPase) catalyzes the conversion of Inosine Triphosphate (ITP) to the correspondent monophosphate. The ITPA c.94C > A and g.IVS2 + 21A > C allelic variants are associated with decreased red cell enzyme activity. The ITPA c.94C > A [P32T] sequence variant is associated with an increased risk of adverse drug reactions in patients treated with the thiopurine drug azathioprine. The aim of this study was to explore the molecular mechanisms of ITPase deficiency. ITPA mRNA was extracted from peripheral blood leukocytes (PBL), Epstein-Barr virus transformed lymphoblast cell cultures, reticulocytes, and cultured fibroblast from patients with known ITPA genotypes. ITPA mRNA was reversed transcribed, sequenced and the relative amounts of misspliced transcripts quantitated from three independent experiments. The ITPA g.IVS2 + 21A > C sequence variant resulted in missplicing of exon 3. The ITPA c.94C > A allelic variant resulted in missplicing of exons 2 and 3 representing, in PBL samples, 61% of the total mRNA expressed in ITPA c.94C > A homozygotes. We proposed that the ITPA c.94C > A allelic variant destroys an exonic splicing silencing (ESS) element in exon 2, resulting in the activation of two nearby upstream 5' splice sites and missplicing of the exons 2 and 3 cassette causing structural changes to the enzyme and contributing to ITPase deficiency. (c) 2006 Elsevier B.V. All rights reserved.

  • genetic basis of Inosine Triphosphate pyrophosphohydrolase deficiency in the japanese population
    Molecular Genetics and Metabolism, 2005
    Co-Authors: Tohru Maeda, Anthony M. Marinaki, Akihito Ueta, Satoshi Sumi, Yumiko Ohkubo, Yukihisa Kurono, Shinsaku Hasegawa, Hajime Togari
    Abstract:

    Abstract Inosine Triphosphate pyrophosphohydrolase (ITPase) is an enzyme that catalyzes the conversion of Inosine Triphosphate (ITP) to Inosine monophosphate and pyrophosphate. In Caucasian populations it is reported that the frequency of cases showing decreased ITPase activity is 5%. The structure of ITPA gene along with five single nucleotide polymorphisms has been reported in Caucasians. We examined ITPase activity and frequency of two polymorphisms (94C > A and IVS2 + 21A > C) in 100 Japanese individuals. Among these individuals, we observed that three cases with zero activity were homozygote for 94C > A, and were accompanied by abnormal accumulation of ITP in erythrocytes. The cases included in the low ITPase activity group were heterozygote for 94C > A polymorphism. The activity of the heterozygote cases was approximately 27% of the mean value of the wild type. The allele frequency of the 94C > A polymorphism was 0.155, which was 2.6 times higher than that of the Caucasians (0.06). The IVS2 + 21A > C was not detected in Japanese cases, although it occurred with a frequency of 0.130 in Caucasians. Furthermore, we identified a novel mutation IVS2 + 68T > G in intron 2 in the case with the lowest enzyme activity in the 94C > A wild type. Since the frequency of ITPA 94C > A polymorphism is higher in the Japanese population than that in Caucasians, it is more important to examine ITPA 94C > A polymorphism in the Japanese population to prevent thiopurine drug toxicity. Pretherapeutic screening of individuals for ITPA polymorphisms should be considered for safer and more tolerable treatment with thiopurine drugs.

  • Allele frequency of Inosine Triphosphate pyrophosphatase gene polymorphisms in a Japanese population.
    Nucleosides Nucleotides and Nucleic Acids, 2004
    Co-Authors: Anthony M. Marinaki, S. Sumi, M. Arenas, Lynette D. Fairbanks, S. Harihara, K. Shimizu, Akihito Ueta, John A. Duley
    Abstract:

    The enzyme Inosine Triphosphate pyrophosphatase (ITPase) catalyses the pyrophosphohydrolysis of ITP to IMP. ITPase deficiency is a clinically benign autosomal recessive condition characterised by the abnormal accumulation of ITP in erythrocytes. A deficiency of ITPase may predict adverse reactions to therapy with the thiopurine drug 6-mercaptopurine and its prodrug azathioprine. In this study, we examine the frequencies of ITPA polymorphisms in 100 healthy Japanese individuals. The allele frequency of the 94C > A variant in the Japanese sample was 0.135 (Caucasian allele frequency 0.06). The IV2 + 21A > C polymorphism was not found in Japanese (Caucasian allele frequency 0.130). Allele frequencies of the 138G > A, 561G > A and 708G > A polymorphisms were 0.57, 0.18 and 0.06 respectively in the Japanese population, and with the exception of the 138G > A polymorphism, similar to allele frequencies in Caucasians.

  • adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding Inosine Triphosphate pyrophosphatase itpase
    Pharmacogenetics, 2004
    Co-Authors: Anthony M. Marinaki, M. Arenas, Lynette D. Fairbanks, Satoshi Sumi, A Ansari, J A Duley, Cathryn M Lewis, Elmonsor Shobowalebakre, Emilia Escuredo, Jeremy D Sanderson
    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.

Yoon Suk Jung - One of the best experts on this subject based on the ideXlab platform.

Maria Shipkova - One of the best experts on this subject based on the ideXlab platform.

  • association between adverse effects under azathioprine therapy and Inosine Triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease
    Therapeutic Drug Monitoring, 2011
    Co-Authors: Maria Shipkova, Jutta Franz, Manabu Abe, Corinne Klett, Eberhard Wieland, Tilo Andus
    Abstract:

    Background: Inosine Triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of Inosine Triphosphate to Inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). Methods: Patients suffering from inflammatory bowel disease who were treated with AZA (N = 160; age 43 ± 12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotrasnferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2 + 21A>C genotypes were determined. Results: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 μmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 μmol/(gHb·h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 μmol/(gHb·h)] were associated with a higher incidence of increased liver enzymes. Conclusions: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.

  • Association between adverse effects under azathioprine therapy and Inosine Triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease.
    Therapeutic drug monitoring, 2011
    Co-Authors: Maria Shipkova, Jutta Franz, Manabu Abe, Corinne Klett, Eberhard Wieland, Tilo Andus
    Abstract:

    Background: Inosine Triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of Inosine Triphosphate to Inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). Methods: Patients suffering from inflammatory bowel disease who were treated with AZA (N = 160; age 43 ± 12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotrasnferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2 + 21A>C genotypes were determined. Results: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 μmol/(gHb·h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly

  • analysis of itpa phenotype genotype correlation in the bulgarian population revealed a novel gene variant in exon 6
    Therapeutic Drug Monitoring, 2007
    Co-Authors: Srebrena Atanasova, Maria Shipkova, Eberhard Wieland, Michael Oellerich, Dobrin Svinarov, Antoaneta Mladenova, Mariana Genova, Nicolas Von Ahsen
    Abstract:

    Abstract:Mutations in the Inosine Triphosphate pyrophosphohydrolase (ITPA) gene causing enzyme deficiency were shown to have pharmacogenetic implications in azathioprine-induced adverse drug reactions. The distribution of ITPA activity as well as the types and the frequencies of gene variants associ

  • measurement of erythrocyte Inosine Triphosphate pyrophosphohydrolase itpa activity by hplc and correlation of itpa genotype phenotype in a caucasian population
    Clinical Chemistry, 2006
    Co-Authors: Maria Shipkova, Eberhard Wieland, Kristin Lorenz, Michael Oellerich, Nicolas Von Ahsen
    Abstract:

    Background: Inosine Triphosphate (ITP) pyrophosphohydrolase (ITPA) catalyzes the pyrophosphohydrolysis of ITP/dITP and xanthosine Triphosphate to prevent incorporation of unusual nucleotides into RNA and DNA. Important mutations leading to enzyme deficiency are 94C>A and IVS2 + 21A>C. An association between ITPA 94C>A and adverse reactions during azathioprine treatment has been shown. To investigate the ITPA phenotype, an HPLC procedure was developed and phenotype-genotype correlations were assessed. Methods: The enzymatic conversion of ITP to Inosine monophosphate (IMP) was terminated by perchloric acid and saturated dipotassium hydrogen phosphate. We quantified the IMP at 262 nm after separation on an Aqua perfect C18 column using 20 mmol/L phosphate buffer, pH 2.5. We also genotyped samples for ITPA 94C>A and IVS2 + 21A>C by real-time fluorescence PCR. Results: The assay was linear to 3 mmol/L IMP [∼500 μmol/(g Hb · h)] with a lower limit of quantification of 4 μmol/L [∼0.5 μmol/(g Hb · h)]. With IMP-enriched samples, within- and between-day imprecision was ≤3.6% and ≤4.9%, respectively, and the inaccuracy was ≤5.2%. With pooled erythrocytes, within- and between-day imprecision was 3.8% and 7.5%, respectively. ITPA activity in 130 healthy controls was between A) and 0.131 (IVS2 + 21A>C). When we used a cutoff of 125 μmol IMP/(g Hb · h), phenotyping detected all 94C>A mutant cases, all 94C>A and IVS2 + 21A>C compound heterozygotes, all IVS2 + 21A>C homozygotes, and 6 of 24 IVS2 + 21A>C heterozygote-only cases. A novel IVS2 + 68T>C mutation was also found. Conclusions: The HPLC procedure provides an excellent ITPA phenotype-genotype correlation and led to the discovery of a novel IVS2 + 68T>C mutation. The method could facilitate investigation of the role of ITPA activity for drug toxicity during thiopurine therapy.