ArticleEuropean journal of clinical pharmacology2012
Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia.
Article in European journal of clinical pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 37 citations in OpenAlex.
- Pharmacogenomics of Thiopurine Drugs: A Bench-To-Bedside Success Story in Thailand.Clinical and translational science · 2026Review
- Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Association ofGenes · 2020Article
- 2SNP heritability and effects of genetic variants for neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio.Journal of human genetics · 2017Article
- Ordinary differential equations and Boolean networks in application to modelling of 6-mercaptopurine metabolism.Royal Society open science · 2017Article
- Germline oncopharmacogenetics, a promising field in cancer therapy.Cellular oncology (Dordrecht, Netherlands) · 2015Review
- Thiopurine methyltransferase polymorphisms in children with acute lymphoblastic leukemia.Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology · 2014Article
- Monitoring thiopurine metabolites in korean pediatric patients with inflammatory bowel disease.Yonsei medical journal · 2014Article
- Article
- Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance.Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology · 2014Article
- Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia.European journal of clinical pharmacology · 2012Review
- Influence of age, sex, and haplotypes of thiopurine methyltransferase (TPMT) gene on 6- mercaptopurine toxicity in children with acute lymphoblastic leukemia.European journal of clinical pharmacology · 2012Article
- Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with thiopurines in patients with acute lymphoblastic leukemia.Frontiers in genetics · 2012Article
- Article
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7 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
purposeTo explore the role of genetic variants of thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) in 6-mercaptopurine (6-MP)-induced toxicity in Indian children with acute lymphoblastic leukemia (ALL).
methodsChildren with ALL receiving 6-MP in maintenance phase of treatment (n = 90) were enrolled in the study. Bidirectional sequencing of TPMT (whole gene) and ITPA (exon 2, exon 3, and intron 2) was undertaken, and correlation between genotype and 6-MP toxicity was assessed.
resultsFive variations were observed in TPMT, including two exonic variations, TPMT*12 (374 C > T) and TPMT*3C (719A > G), and three intronic, intron 3 (12356 C > T), intron 4 (16638 C > T), and TPMT rs2842949. Two exonic, ITPA exon -2 (94 C → A) and exon 3 of ITPA (138 G > A), and one intronic, ITPA intron 2 (A→C), variations were observed in ITPA. Multifactor dimensionality reduction analysis of all the genetic variants showed independent association of ITPA 94 C→A as well as synergic epistatic interactions, i.e., TPMT*12 × ITPA ex3, ITPA ex2 × TPMT*12 × ITPA ex3, and TPMT*3C × ITPA ex2 × TPMT*12 × ITPA ex3, in determining hematological toxicity. This is further substantiated by a multiple linear regression model, which showed moderate predictability of toxicity with these variants (area under the curve = 0.70, p = 0.004).
conclusionOur 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.
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