Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk

Nguyen, Christine M.; Mendes, Margaret; Joseph, D.

doi:10.1371/currents.rrn1236

Cited by 53 publications

(38 citation statements)

References 28 publications

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“…However, there is no consensus regarding the merit of genotyping for TPMT deficiency and related myelotoxicity since TPMT genotype is not the only cause of myelotoxicity [72,88].…”

Section: Pharmacokinetic and Pharmacodynamic Considerationsmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

et al. 2018

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“…However, there is no consensus regarding the merit of genotyping for TPMT deficiency and related myelotoxicity since TPMT genotype is not the only cause of myelotoxicity [72,88].…”

Section: Pharmacokinetic and Pharmacodynamic Considerationsmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

et al. 2018

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“…3,4 The risk for azathioprine-induced myelosuppression is particularly high in patients with reduced activity of thiopurine Smethyltransferase (TPMT), an enzyme involved in the metabolism of azathioprine. 5 Polymorphisms in TPMT result in variation in enzymatic activity, thiopurine drug effect, and toxicity. 6 Individuals with the homozygous wild-type TPMT genotype (*1) have normal enzymatic activity, whereas those with a variant allele (heterozygous) have deficient enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

“…6 Individuals with the homozygous wild-type TPMT genotype (*1) have normal enzymatic activity, whereas those with a variant allele (heterozygous) have deficient enzymatic activity. 5 Three variant alleles are responsible for 80% to 95% of intermediate and low TPMT enzyme activity: TPMT*2 (G238C; Ala80→Pro), TPMT*3A (G460A and A719G; Ala154→Τhr and Tyr240→Cys), and TPMT*3C (A719G; Tyr240→Cys). 7,8 In this analysis we sought to investigate the frequency of TPMT genetic variation in a large, multicenter cohort of pediatric HT recipients and to assess whether azathioprine-treated recipients with TPMT variants were at increased risk of infection.…”

Section: Introductionmentioning

confidence: 99%

Association Between Thiopurine S-Methyltransferase (TPMT) Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis

Green¹,

Duong²,

Burckart³

et al. 2018

The Journal of Pediatric Pharmacology and Therapeutics

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OBJECTIVES Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. METHODSWe genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups.RESULTS TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0-6 versus 0.5 ± 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. CONCLUSIONSIn this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.

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confidence: 99%

“…Four alleles *2 (c.G238C, rs1800462), *3A (c.G460A, rs1800460 and c.A719G, rs1142345), *3B (c.G460A, rs1800460), and *3C (c.A719G, rs1142345)have been associated with decreased TPMT enzyme activity and increased myelosuppression risk (8). TPMT genotyping is therefore useful to predict this risk (8). Approximately 89% of the Caucasian population studied are homozygous wild type and show no variations, resulting in normal enzyme activity; 11% are heterozygous with intermediate activity; and 1 out of every 300 subjects are homozygous for the trait with a low level of red blood cell TPMT activity (9).…”

mentioning

confidence: 99%

Alternative Method of Allelic Discrimination

2014

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5' nuclease assays for allelic discrimination use both a wild-type and a mutant probe. Here we present a new method for genotyping by 5' nuclease assays that dispenses with the mutant probe, using the wild-type probe together with a probe for a reference gene known to be present in two copies to determine the copy number of the wild type allele relative to the reference gene. The copy number of the wild-type allele then determines the genotype: two copies indicates homozygous wild-type; one copy indicates heterozygous; and zero copies indicates homozygous mutant. We were able to use our method to correctly genotype three alleles of the thiopurine methyl transferase (TPMT) gene: TPMT *2 (c.G238C), *3B (c.G460A) and *3C (c.A719G). Our approach can be used as an alternate allelic discrimination strategy that is cost effective when multiple TaqMan assays are performed on a sample.

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Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk

Cited by 53 publications

References 28 publications

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

Association Between Thiopurine S-Methyltransferase (TPMT) Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis

Alternative Method of Allelic Discrimination

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