Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Dorababu, Patchva; Nagesh, Narayana; Linga, Vijay Gandhi; Gundeti, Sadashivudu; Kutala, Vijay Kumar; Reddanna, Pallu; Digumarti, Raghunadharao

doi:10.1007/s00228-011-1133-1

Cited by 30 publications

(17 citation statements)

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“…The difference in the incidence of polymorphic allele from Caucasians is the other explanation for the discrepancies. In addition, there are many other genes which involve the metabolism of mercaptopurine, and synergistic epistatic interaction within these genes was recently reported as an influencing factor for hematological toxicity of mercaptopurine [29]. Dorababu et al reported that epistatic interactions between the variations of TPMT (*3C, *12) and ITPA (rs1127354, rs8362) were associated with the 6-MP toxicity by multifactor dimensionality reduction analysis [29].…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

et al. 2012

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Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

et al. 2012

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“…All nine exons of the TPMT gene were amplified on a model 9700 thermal cycler (Applied Biosystems, Foster City, CA, USA) using oligonucleotide primers and conditions as previously described with some modifications 20,21. Direct sequencing was performed using ABI Big Dye Terminator kit v1.1 (Applied Biosystems) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Monitoring Thiopurine Metabolites in Korean Pediatric Patients with Inflammatory Bowel Disease

2014

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PurposeThis study aimed to assess the role of thiopurine S-methyltransferase (TPMT) and 6-thioguanine nucleotide (6-TGN) as predictors of clinical response and side effects to azathioprine (AZA), and estimate the optimal AZA dose in Korean pediatric inflammatory bowel disease (IBD) patients.Materials and MethodsOne hundred and nine pediatric IBD patients in whom AZA treatment was required were enrolled. Thiopurine metabolites were monitored since September 2010. Among them, 83 patients who had prescribed AZA for at least 3 months prior to September 2010 were enrolled and followed until October 2011 to evaluate optimal AZA dose, adverse effects and disease activity before and after thiopurine metabolite monitoring.ResultsThe result of the TPMT genotype was that 102 patients were *1/*1 (wild type), four were *1/*3C, one was *1/*6, one was *1/*16 (heterozygote) and one was *3C/*3C (homozygote). Adverse effects happened in 31 patients pre-metabolite monitoring and in only nine patients post-metabolite monitoring. AZA dose was 1.4±0.31 mg/kg/day before monitoring and 1.1±0.46 mg/kg/day after monitoring (p<0.001). However, there were no statistical differences in disease activity during metabolite monitoring period (p=0.34). Adverse effects noticeably decreased although reduction of the AZA dose since monitoring.ConclusionTPMT genotype and thiopurine metabolite monitoring could be helpful to examine TPMT genotypes before administering AZA and to measure 6-TGN concentrations during prescribing AZA in IBD patients.

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“…The potential implication of ITPA in the occurrence of ADRs of AZA has been investigated. However, a number of contradictory results have been reported, from an impact of ITPA polymorphism on toxicity to no significant association . This issue remains unresolved, and no obvious statement about the benefit of introducing ITPA assay into clinical practice is currently available .…”

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.

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Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Abstract: Our results suggest that apart from the individual effect of ITPA 94 C→A, epistatic interactions between the variations of TPMT (3C, 12) and ITPA (ex2, ex3) are associated with the 6-MP toxicity. Testing these variants facilitates tailoring of the 6-MP therapy in children with ALL.

Cited by 30 publications

References 36 publications

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

Monitoring Thiopurine Metabolites in Korean Pediatric Patients with Inflammatory Bowel Disease

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

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Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Abstract: Our results suggest that apart from the individual effect of ITPA 94 C→A, epistatic interactions between the variations of TPMT (*3C, *12) and ITPA (ex2, ex3) are associated with the 6-MP toxicity. Testing these variants facilitates tailoring of the 6-MP therapy in children with ALL.

Cited by 30 publications

References 36 publications

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

Monitoring Thiopurine Metabolites in Korean Pediatric Patients with Inflammatory Bowel Disease

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

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Abstract: Our results suggest that apart from the individual effect of ITPA 94 C→A, epistatic interactions between the variations of TPMT (3C, 12) and ITPA (ex2, ex3) are associated with the 6-MP toxicity. Testing these variants facilitates tailoring of the 6-MP therapy in children with ALL.