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Thiopurine methyltransferase

Riin Tamm, Reedik Mägi, Roman Tremmel, Stefan Winter, Evelin Mihailov, Alenka Smid, Anja Möricke, Kathrin Klein, Martin Schrappe, Martin Stanulla, Richard Houlston, Richard Weinshilboum, Irena Mlinarič Raščan, Andres Metspalu, Lili Milani, Matthias Schwab, Elke Schaeffeler
Thiopurine-related hematotoxicity in paediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 paediatric ALL-cases...
October 22, 2016: Clinical Pharmacology and Therapeutics
David A Khan
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively...
October 2016: Journal of Allergy and Clinical Immunology
Marianne Kiszka-Kanowitz, Klaus Theede, Anette Mertz-Nielsen
BACKGROUND: Treating inflammatory bowel diseases (IBD) using thiopurines is effective; however, a high rate of adverse effects and lack of efficacy limit its use. Retrospective studies have suggested that treatment with low-dose thiopurines in combination with allopurinol is associated with higher remission rates and lower incidence of adverse events. AIM: To compare the rates of clinical remission and the rates of adverse events in IBD patients treated with either standard treatment with azathioprine or low-dose azathioprine in combination with allopurinol...
December 2016: Scandinavian Journal of Gastroenterology
Angela Di Salvo, Carmelo Fabiano, Vincenza Mannara, Mariangela Dimarco, Ambrogio Orlando, Marco Affronti, Fabio Salvatore Macaluso, Mario Cottone
BACKGROUND AND AIMS: Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype. RESULTS: Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0...
September 1, 2016: Digestive and Liver Disease
Alison L T Ma, Gregory Bale, Helen Aitkenhead, Stephen D Marks
OBJECTIVE: To assess the profile of thiopurine transmethyltransferase (TPMT) enzyme activities in children and discuss the utility of measuring TPMT levels before commencing azathioprine therapy. STUDY DESIGN: Retrospective study in a single pediatric center of all patients who had TPMT enzyme assay measured during a 3-year period before the start of azathioprine therapy. Patients' TPMT enzyme activities were classified as normal (26-50 pmol/h/mgHb), intermediate (10-25 pmol/h/mgHb), and deficient (<10 pmol/h/mgHb)...
September 15, 2016: Journal of Pediatrics
X Zhu, X-D Wang, K Chao, M Zhi, H Zheng, H-L Ruan, S Xin, N Ding, P-J Hu, M Huang, X Gao
BACKGROUND: Thiopurine-induced leukopenia is the most common dangerous adverse event in Asians. NUDT15 R139C was recently proposed to be a promising biomarker for leukopenia with thiopurine therapy in Asians, but this has not been replicated in the Chinese population. AIM: To investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), 6-TGN and 6-MMPR on thiopurine-induced leukopenia in Chinese patients with Crohn's disease. METHODS: Clinical and epidemiological characteristics were reviewed from medical records...
November 2016: Alimentary Pharmacology & Therapeutics
Ingolf Cascorbi, Anneke Nina Werk
INTRODUCTION: Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. AREAS COVERED: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC)...
September 16, 2016: Expert Opinion on Drug Metabolism & Toxicology
Nathalie K Zgheib, Reem Akika, Rami Mahfouz, Carol Al Aridi, Khaled M Ghanem, Raya Saab, Miguel R Abboud, Nidale Tarek, Hassan El Solh, Samar A Muwakkit
BACKGROUND: Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases...
August 31, 2016: Pediatric Blood & Cancer
Chengcheng Liu, Wenjian Yang, Deqing Pei, Cheng Cheng, Colton Smith, Wendy Landier, Lindsey Hageman, Yanjun Chen, Jun J Yang, Kristine R Crews, Nancy Kornegay, Seth E Karol, F Lennie Wong, Sima Jeha, John T Sandlund, Raul R Ribeiro, Jeffrey E Rubnitz, Monika L Metzger, Ching-Hon Pui, William E Evans, Smita Bhatia, Mary V Relling
We performed a genome-wide association study of primary erythrocyte TPMT activity in children with leukemia (n = 1026). Adjusting for age and ancestry, TPMT was the only gene that reached genome-wide significance (top hit rs1142345 or 719A>G, P = 8.6 × 10(-61) ). Additional genetic variants (besides the 3 SNPs rs1800462, rs1800460 and rs1142345 defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2...
August 26, 2016: Clinical Pharmacology and Therapeutics
Amine Benmassaoud, Xuanqian Xie, Motaz AlYafi, Yves Theoret, Alain Bitton, Waqqas Afif, Talat Bessissow
Background and Aims. Thiopurines are used in the treatment of Crohn's disease (CD) and thiopurine S-methyltransferase (TPMT) activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT. Methods. This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb) who were followed for 1 year. Patients started at full dose of azathioprine (2-2...
2016: Canadian Journal of Gastroenterology & Hepatology
Nataša Karas-Kuželički, Simona Mencej-Bedrač, Janez Jazbec, Janja Marc, Irena Mlinarič-Raščan
Treatment induced non-traumatic osteonecrosis (ON) has been reported increasingly in children treated for acute lymphoblastic leukemia (ALL). Several risk factors for ON have been identified in childhood cancer patients; however, their diagnostic and prognostic power is limited and the etiology of the disease remains unclear. Therefore, a continuous effort is focused on the identification of additional ON risk factors. We performed a retrospective study of 313 childhood ALL patients to test the association between the ON occurrence in children receiving ALL therapy and common polymorphisms in potential target genes: Thiopurine S-methyltransferase (TPMT; 460G>A, 719A>G), 5,10-methylenetetrahydrofolate reductase (MTHFR; 677C>T, 1298A>C), estrogen receptor alpha 1 (ESR1; XbaI) and collagen type I, α1 (COL1A1; Sp1)...
August 2016: Experimental and Therapeutic Medicine
B S Muller, H F van Goor, A J W P Rosenberg
A 51-year-old man was referred by his dentist to a maxillofacial surgeon with complaints of illness and pain in the mandible, associated with a rapidly expanding area of black gingiva and mucosa surrounding the lower front teeth. Clinically and radiographically there was evidence of an infected necrosis of the chin and floor of mouth. Following debridement at the operating room, the patient was treated at the intensive care unit for septic shock leading to prolonged hospitalisation. Investigation of the bone marrow did not provide an explanation for pancytopenia or the severity of the illness...
July 2016: Nederlands Tijdschrift Voor Tandheelkunde
Swarup A V Shah, Minal Paradkar, Devendra Desai, Tester F Ashavaid
BACKGROUND & AIM: Inter-individual variation seen in the thiopurine metabolism is attributed to the genetic variant in Thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and it's association with thiopurine-induced toxicity in Indian patients...
July 15, 2016: Journal of Gastroenterology and Hepatology
Cristina Martínez Faci, Ignacio Ros Arnal, José M Martínez de Zabarte Fernández, Jordi Sorribes Estorch, Mónica López Campos, Carmen Rodríguez-Vigil Iturrate
Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts...
August 1, 2016: Archivos Argentinos de Pediatría
May Fakhoury, Evelyne Jacqz-Aigrain, Tiphaine de Beaumais, Yves Médard
6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis...
May 2010: Thérapie
Shunsuke Kimura, Daisuke Hasegawa, Yuri Yoshimoto, Shinsuke Hirabayashi, Yosuke Hosoya, Hiroki Yoshihara, Tadashi Kumamoto, Yoichi Tanaka, Atsushi Manabe
Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days...
June 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Z Ailing, Y Jing, L Jingli, X Yun, Z Xiaojian
WHAT IS KNOWN AND OBJECTIVE: Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians...
October 2016: Journal of Clinical Pharmacy and Therapeutics
Agata Ladić, Nada Božina, Vladimir Borzan, Marko Brinar, Boris Vucelić, Silvija Cuković-Cavka
Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reaction-based assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers...
March 2016: Acta Clinica Croatica
Marzena Skrzypczak-Zielinska, Pawel Borun, Anna Bartkowiak-Kaczmarek, Oliwia Zakerska-Banaszak, Michal Walczak, Agnieszka Dobrowolska, Mateusz Kurzawski, Malgorzata Waszak, Daniel Lipinski, Andrzej Plawski, Ryszard Slomski
Thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA) are crucial enzymes involved in the metabolism of thiopurine drugs: azathioprine and 6-mercaptopurine, used in the treatment of leukemia or inflammatory bowel diseases (IBD). The activity in these enzymes correlates with the genetic polymorphism of the TPMT and ITPA genes, respectively, which determines an individual reaction and dosing of thiopurines. Three main TPMT alleles: TPMT*2 (c.238G>C), TPMT*3A (c.460G>A, c.719A>G) and TPMT*3C (c...
October 2016: Molecular Diagnosis & Therapy
R M Zur, L M Roy, S Ito, J Beyene, C Carew, W J Ungar
Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta-analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90...
August 2016: Pharmacogenomics Journal
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