TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment

Song, Dongjian; Zhao, Jin’an; Zhang, L.‐R.

doi:10.1111/j.1365-2710.2006.00775.x

Cited by 22 publications

(9 citation statements)

References 29 publications

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“…Recently, genetic polymorphisms of TPMT and NUDT15 have been proposed to be involved with an increased risk of myelosuppression in patients treated with thiopurine drugs, including 6-MP and its prodrug, azathioprine. 4,8,9,14,15,18,19 To the authors' knowledge, this is the first study evaluating the common TPMT variant and all known loss-of-function NUDT15 variants in Thai pediatric ALL patients.…”

Section: Discussionmentioning

confidence: 99%

“…7 Several studies have demonstrated that individuals who carry these variant alleles may be at a higher risk of severe myelosuppression when treated with 6-MP or 6-MP derivatives. 7,8 In contrast to TPMT, NUDT15 genetic polymorphism is more common in Asian populations than in Caucasian populations. Phenotypes of more than 10 variant alleles of NUDT15 have been extensively characterized.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

et al. 2020

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Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2, NUDT15*5, and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

et al. 2020

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“…Kurzawski et al [18] demonstrated that the number of HZ renal transplant patients (n=2, 15%) who experienced rejection were similar to WT (n=20, 20%). Amongst the 8 HZ renal transplant recipients in a study by Song et al, [19] there was a trend towards increased rejection in HZ (25%) as compared to WT patients (21.9%). In both studies, the starting AZA dose was not adjusted based on genotype, so the implications for a reduced AZA dose are unknown.…”

Section: Discussionmentioning

confidence: 99%

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation

Liang¹,

Geske

Boilson³

et al. 2013

Pharmacogenetics and Genomics

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Objectives Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose due to higher active metabolite levels and risk of adverse events. However, in vitro lymphocyte proliferation assays performed in subjects with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared to wild type (WT) subjects. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. Methods We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored for by routine endomyocardial biopsies. Results There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared to WT (13.1± 2.8 vs. 21 ± 4.5 U/mL RBC, p<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (p<0.001), and total rejection score was higher (p=0.02) than WT. AZA was discontinued more frequently in HZ (p=0.01) due to rejection. Incidence of leukopenia was similar between groups (40% vs. 43%, p=1.0). Conclusion HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.

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“…In this regard, a number of studies have indicated that there is a significant negative correlation between the intracellular concentration of TGNs and TPMT activity in erythrocytes [Lennard, 1990;] and TGN concentrations are associated with the efficacy and toxicity of thiopurines in various diseases including leukemia and IBD [Chrzanowska et al, 2006;Davison et al, 2006;de Boer et al, 2007;Dervieux et al, 1999;Dokmanovic et al, 2006;Evans et al, 1991;Gisbert, 2006;Lennard and Lilleyman, 1989;Lennard et al, 2006;Lennard et al, 1997;Morales et al, 2006;Schedel et al, 2006;Song et al, 2006].…”

Section: Genotype-phenotype Relationshipsmentioning

confidence: 99%

Clinical Significance of Thiopurine S-Methyltransferase Gene Polymorphisms

Zhou¹,

Chowbay

2007

CPG

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Thiopurine methyltransferase (TPMT) is an important enzyme that catalyzes the S-methylation of a series of thiopurine drugs, including 6-mercaptopurine (6-MP), thioguanine and azathiopurine (AZA), to generate inactive methylated metabolites. Thiopurine drugs are widely used to treat malignancies such as acute lymphoblastic leukemia, autoimmune diseases (e.g. inflammatory bowel disease and rheumatoid arthritis), and organ transplant rejection. TPMT activity and TPMT gene exhibit marked polymorphic phenomenon among all ethnic populations studied, though ethnic differences are always observed. To date, a number of TPMT alleles have been identified. The three major alleles of TPMT, namely TPMT *2, *3A and *3C, lead to intermediate and low enzyme activity in 80-95% carriers. Almost all alleles of TPMT result from single nucleotide polymorphisms (SNPs). Patients with very low levels of TPMT activity due to genetic mutation suffer from greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of thiopurine drugs, while subjects with very high activity may be under-treated. Drug interactions, less frequently observed, may occur due to TMPT induction or inhibition when thiopurine drugs are combined with other agents. It is important to identify the TPMT mutant alleles with functional impact and the clinical relevance to thiopurine therapy. This allows us to avoid severe toxicity and improve therapeutic outcome by tailoring dosage and regimens in individual patients.

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TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment

Abstract: Our results, together with those of others pointing in the same direction, suggest that genotyping the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.

Cited by 22 publications

References 29 publications

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation

Clinical Significance of Thiopurine S-Methyltransferase Gene Polymorphisms

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