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Polymorphic variation in TPMT is the principal determinant of TPMT phenotype [El. vir] : a meta-analysis of three genome-wide association studiesTamm, Riin ...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. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including TPMT gene region, were significantly associated with TPMT activity (P<5x10 -8) in each of the three GWAS and a joint meta-analysis of 1212 cases (top hit P=1.2x10 -72). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize MP dosage. This article is protected by copyright. All rights reserved.Source: Clinical pharmacology & therapeutics [Elektronski vir]. - ISSN 1532-6535 (Vol. 101, no. 5, May 2017, str. 684-695)Type of material - e-articlePublish date - 2017Language - englishCOBISS.SI-ID - 4231793
Author
Tamm, Riin |
Mägi, Reedik |
Tremmel, Roman |
Winter, Stefan, pharmacologist |
Mihailov, Evelin |
Šmid, Alenka, farmacevtka |
Möricke, Anja |
Klein, Kathrin |
Schrappe, Martin |
Stanulla, Martin |
Houlston, RIchard |
Weinshilboum, Richard |
Mlinarič-Raščan, Irena |
Metspalu, Andres |
Milani, Lili |
Schwab, Matthias |
Schaeffeler, Elke
Topics
pharmacogenetics |
personalized medicine |
phase II |
liver |
polymorphism
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Tamm, Riin | |
Mägi, Reedik | |
Tremmel, Roman | |
Winter, Stefan, pharmacologist | |
Mihailov, Evelin | |
Šmid, Alenka, farmacevtka | 29982 |
Möricke, Anja | |
Klein, Kathrin | |
Schrappe, Martin | |
Stanulla, Martin | |
Houlston, RIchard | |
Weinshilboum, Richard | |
Mlinarič-Raščan, Irena | 12443 |
Metspalu, Andres | |
Milani, Lili | |
Schwab, Matthias | |
Schaeffeler, Elke |
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