Dataset Information

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

ABSTRACT: 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. METHODS:We 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. CONCLUSIONS:In 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.

SUBMITTER: Green DJ

PROVIDER: S-EPMC5916437 | biostudies-literature | 2018 Mar-Apr

REPOSITORIES: biostudies-literature

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

Green Dionna J DJ Duong Son Q SQ Burckart Gilbert J GJ Sissung Tristan T Price Douglas K DK Figg William D WD Brooks Maria M MM Chinnock Richard R Canter Charles C Addonizio Linda L Bernstein Daniel D Naftel David C DC Zeevi Adriana A Kirklin James K JK Webber Steven A SA Feingold Brian B

The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG 20180301 2

<h4>Objectives</h4>Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine <i>S</i>-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 <i>TPMT</i> genetic variation and assessed whether azathioprine-treated recipients with <i>TPMT</i> v ...[more]

PMID: 29720911

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Project description:Pediatric Crohn's disease (CD) carries a higher genetic susceptibility and an increased risk of a more aggressive disease course than adult CD. Treatment of CD is based on immunomodulatory drugs, such as thiopurines. The enzyme mainly involved in drug metabolism is thiopurine S-methyltransferase (TPMT). An increased concentration of drug metabolites can cause adverse drug effects, such as myelosuppression and hepatotoxicity; therefore, assessing the activity of TPMT is essential both before and during treatment. TPMT genotyping result is not affected by previous thiopurine dose and currently is the primary component of TPMT activity and disease monitoring. Until now, more than 40 allelic variants of the TPMT gene have been reported, with most of them having an uncertain or no enzyme function. In this article, we report the first case of a novel TPMT allele, TPMT*45, that was identified in a Korean girl with CD whose findings suggested decreased TPMT activity. This newly observed variant is caused by a single nucleotide polymorphism resulting in nonsense mutation (c.676C>T, p.R226*) and the partial loss of amino acids in the TPMT protein. Initially, the patient began azathioprine at a standard dosage (1.5 mg/kg/day), and her laboratory results, including red blood cell (RBC) TPMT activity (6-methylmercaptopurine 2.68 nmol/mL/h and 6-methylmercaptopurine riboside 4.82 nmol/mL/h) along with thiopurine metabolite levels (6-thioguanine nucleotides 479.3 pmol/8×108 RBC), suggested an enzyme deficiency. The thiopurine dose was reduced to half (0.7 mg/kg/day), and the follow-up metabolite results as well as the associated inflammatory markers were continuously within reference ranges. Along with an improvement in the patient's subjective reports and clinical symptoms, the patient demonstrated a good treatment response to the adjusted dose. The results of our report illustrate the importance of TPMT genotyping and pharmacogenetic-based thiopurine dose adjustment. Further research should focus on the functional characterization and impact on this novel allele's treatment effect.

Project description:PurposeAzathioprine (AZA) is widely used as an immunosuppressive drug in autoimmune diseases, but its use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in AZA metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating AZA therapy. Although several studies have investigated the association between TPMT polymorphisms and AZA-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and AZA-induced ADRs using meta-analysis.MethodsWe explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and AZA-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in patients with autoimmune diseases were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using Revman 5.3 software.ResultsEleven published studies, with a total of 651 patients with autoimmune diseases, investigated associations between TPMT polymorphisms and AZA-induced ADRs, were included in this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with AZA-induced overall ADRs, bone marrow toxicity and gastric intolerance; pooled ORs were 3.12 (1.48-6.56), 3.76 (1.97-7.17) and 6.43 (2.04-20.25), respectively. TPMT polymorphisms were not associated with the development of hepatotoxicity; the corresponding pooled OR was 2.86 (95%CI: 0.32-25.86). However, the association in GI subset could be driven by one single study. After this study was excluded, the OR was 2.11 (95%CI: 0.36-12.42); namely, the association became negative.ConclusionsOur meta-analysis demonstrated an association of TPMT polymorphisms with overall AZA-induced ADRs, bone marrow toxicity and gastric intolerance, but not with hepatotoxicity. The presence of the normal TPMT genotypes cannot preclude the development of ADRs during AZA treatment, TPMT genotyping prior to commencing AZA therapy cannot replace, may augment, the current practice of regular monitoring of the white blood cell. Because of small sample sizes, large and extensive exploration was required to validate our findings.

Dataset Information

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

Publications

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

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