Thiopurine-methyltransferase variants in inflammatory bowel disease: Prevalence and toxicity in Brazilian patients

Carvalho, Ana Teresa Pugas; Esberard, Barbara C.; Fróes, Renata S B; Rapozo, Davy; Grinman, Ana; Simão, Tatiana de Almeida; Santos, Juliana C.; Carneiro, Antonio José V.; Pinto, Luís Felipe Ribeiro; Souza, Heitor Siffert Pereira de

doi:10.3748/wjg.v20.i12.3327

Cited by 16 publications

(11 citation statements)

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“…(Genetic) biomarkers for the prediction of the response to therapy are almost only available in the context of azathioprine and 6-mercaptopurine therapy [56][57][58].…”

Section: Introductionmentioning

confidence: 99%

Clinical Utility of Biomarkers in IBD

Rogler

Biedermann

2015

Curr Gastroenterol Rep

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There is no gold standard for the diagnosis and monitoring of inflammatory bowel diseases (IBD). Biomarkers are useful tools for the management of patients suffering from IBD. However, they should be used only when their additional information is useful for clinical decision-making. In principal, four situations during the management of an individual IBD patient can be discriminated from a clinical standpoint in which biomarkers provide useful information. First, biomarkers may be helpful when the diagnosis of IBD is established and aid in the discrimination between ulcerative colitis (UC) and Crohn's disease (CD) is necessary. Second, biomarkers may be helpful in the prognostic evaluation of IBD severity or disease behavior and for early decisions on the best treatment. The third situation in which biomarkers are useful is the evaluation of disease activity during the disease course, for monitoring and for guidance of ongoing treatment. Finally, the fourth typical situation when biomarkers are of value is after surgery to predict or diagnose a relapse of the disease. From a clinical point of view, it may be more useful to discuss specific biomarkers and their individual value and impact in these four prototypic situations than to sum up advantages and disadvantages for each biomarker isolated from the clinical situation. Therefore, this overview is structured in chapters reflecting those four typical situations during the disease course of IBD patents to critically evaluate the potential and value of each of the biomarkers in the specific situation.

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“…(Genetic) biomarkers for the prediction of the response to therapy are almost only available in the context of azathioprine and 6-mercaptopurine therapy [56][57][58].…”

Section: Introductionmentioning

confidence: 99%

Clinical Utility of Biomarkers in IBD

Rogler

Biedermann

2015

Curr Gastroenterol Rep

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“…In addition, whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs is still controversial. For instance, in a study of 219 IBD patients, TPMT polymorphisms were significantly associated with pancreatitis, but were not associated with bone marrow toxicity [ 17 ]. However, these results were contradicted by another study of 93 IBD patients [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Association between Thiopurine S-methyltransferase Polymorphisms and Thiopurine-Induced Adverse Drug Reactions in Patients with Inflammatory Bowel Disease: A Meta-Analysis

Liu

Xiang

et al. 2015

PLoS ONE

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PurposeThiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis.MethodsWe explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software.ResultsFourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82–6.19) and 6.67 (95%CI: 3.88–11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60–2.71), 0.97 (95%CI: 0.38–2.48), 1.82 (95%CI: 0.93–3.53), 1.28 (95%CI: 0.47–3.46) and 2.32 (95%CI: 0.86–6.25), respectively.ConclusionsOur meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up.

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“…Our search identified one study of TPMT and thiopurines in a PGx context in Brazilians. Carvalho et al genotyped TPMT variants in patients with inflammatory bowel disease under treatment with azathioprine. No association was detected regarding myelotoxicity or hepatotoxicity, but a trend towards increased serum levels of pancreatic enzymes was observed in carriers of TPMT*2 and TPMT*3C .…”

Section: Resultsmentioning

confidence: 90%

“…Figure shows a flowchart of our search results. After filtering PubMed entries and publications from REFARGEN members, 72 articles were selected, 22 of which examined both pharmacogene(s) and drug(s) from a CPIC guideline (Table ). The remaining 50 articles investigated one or more genes comprised in the guidelines.…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

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Thiopurine-methyltransferase variants in inflammatory bowel disease: Prevalence and toxicity in Brazilian patients

Abstract: The prevalence of TPMT genotypes was high among Brazilian patients. Variants genes 2 and 3C may be associated with azathioprine pancreatic toxicity in a IBD southeastern Brazilian population.

Cited by 16 publications

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Clinical Utility of Biomarkers in IBD

Clinical Utility of Biomarkers in IBD

Association between Thiopurine S-methyltransferase Polymorphisms and Thiopurine-Induced Adverse Drug Reactions in Patients with Inflammatory Bowel Disease: A Meta-Analysis

Pharmacogenomics research and clinical implementation in Brazil

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