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William E Evans - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of Thiopurine Methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Laura J. Janke, William E Evans, Jun J. Yang, John D. Schuetz, Mary V. RellingAbstract:Purpose Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine Methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Matthias Schwab, Teri E KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine Methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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nomenclature for alleles of the Thiopurine Methyltransferase gene
Pharmacogenetics and Genomics, 2013Co-Authors: Malin Lindqvist Appell, Howard L Mcleod, William E Evans, J A Duley, Mary V. Relling, L Lennard, Jonathan S Berg, Martin A Kennedy, Tony Marinaki, Elke SchaeffelerAbstract:The drug-metabolizing enzyme Thiopurine Methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the Thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing Thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Teri E KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine Methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
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using hapmap tools in pharmacogenomic discovery the Thiopurine Methyltransferase polymorphism
Clinical Pharmacology & Therapeutics, 2007Co-Authors: William E Evans, Mary V. Relling, T S Jones, Wenjian YangAbstract:One purpose of the International HapMap Project is to provide a genome-wide resource to discover pharmacogenetic determinants of drug response. The Thiopurine Methyltransferase (TPMT) 719A>G single-nucleotide polymorphism (SNP) causes decreased TPMT activity, increased intracellular Thiopurines, and drug toxicities. Using HapMap cell lines and 3.3 million SNPs, we tested whether the TPMT 719A>G SNP could be identified as predicting TPMT phenotype. Assuming TPMT was a candidate gene, five SNPs and four haplotypes predicted TPMT phenotype, two of which were in complete linkage disequilibrium with the functional 719A>G SNP. We also used a genome-wide approach to rank all 17,542 genes as predictors of TPMT activity. A TPMT haplotype, HAP1, significantly predicted TPMT phenotype; however, haplotypes of 96 genes ranked higher than TPMT. Our findings show that HapMap resources are useful for pharmacogenetic discovery when the candidate gene is known, but challenges remain for definitive gene identification when a genome-wide agnostic approach is employed.
Mary V. Relling - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of Thiopurine Methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Laura J. Janke, William E Evans, Jun J. Yang, John D. Schuetz, Mary V. RellingAbstract:Purpose Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine Methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Matthias Schwab, Teri E KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine Methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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nomenclature for alleles of the Thiopurine Methyltransferase gene
Pharmacogenetics and Genomics, 2013Co-Authors: Malin Lindqvist Appell, Howard L Mcleod, William E Evans, J A Duley, Mary V. Relling, L Lennard, Jonathan S Berg, Martin A Kennedy, Tony Marinaki, Elke SchaeffelerAbstract:The drug-metabolizing enzyme Thiopurine Methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the Thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing Thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Teri E KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine Methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
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using hapmap tools in pharmacogenomic discovery the Thiopurine Methyltransferase polymorphism
Clinical Pharmacology & Therapeutics, 2007Co-Authors: William E Evans, Mary V. Relling, T S Jones, Wenjian YangAbstract:One purpose of the International HapMap Project is to provide a genome-wide resource to discover pharmacogenetic determinants of drug response. The Thiopurine Methyltransferase (TPMT) 719A>G single-nucleotide polymorphism (SNP) causes decreased TPMT activity, increased intracellular Thiopurines, and drug toxicities. Using HapMap cell lines and 3.3 million SNPs, we tested whether the TPMT 719A>G SNP could be identified as predicting TPMT phenotype. Assuming TPMT was a candidate gene, five SNPs and four haplotypes predicted TPMT phenotype, two of which were in complete linkage disequilibrium with the functional 719A>G SNP. We also used a genome-wide approach to rank all 17,542 genes as predictors of TPMT activity. A TPMT haplotype, HAP1, significantly predicted TPMT phenotype; however, haplotypes of 96 genes ranked higher than TPMT. Our findings show that HapMap resources are useful for pharmacogenetic discovery when the candidate gene is known, but challenges remain for definitive gene identification when a genome-wide agnostic approach is employed.
Teri E Klein - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Matthias Schwab, Teri E KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine Methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Teri E KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine Methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
Kjeld Schmiegelow - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing 2013 update
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, J K Hicks, Matthias Schwab, Teri E KleinAbstract:The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on Thiopurine Methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and Thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As Thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).
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clinical pharmacogenetics implementation consortium guidelines for Thiopurine Methyltransferase genotype and Thiopurine dosing
Clinical Pharmacology & Therapeutics, 2011Co-Authors: Mary V. Relling, Kjeld Schmiegelow, William E Evans, William J. Sandborn, Eric E Gardner, C M Stein, Michelle Whirl Carrillo, Teri E KleinAbstract:The purpose of this guideline is to provide information with which to interpret clinical Thiopurine Methyltransferase (TPMT) genotype tests so that the results can be used successfully to guide the dosing of Thiopurines. Although most of the dosing recommendations have been generated from clinical studies in only a few diseases, we have extrapolated recommended doses to all conditions, given the pharmacokinetic characteristics of the genotype/phenotype associations. This is the first guideline developed by the Clinical Pharmacogenetics Implementation Consortium, which is part of the National Institutes of Health’s Pharmacogenomics Research Network.1 The consortium is a community-driven organization that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). Guidelines for the use of phenotypic tests (i.e., TPMT activity and Thiopurine metabolite levels) and analyses of cost effectiveness are beyond the scope of this article.
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Thiopurine Methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia results from the nopho all 92 study
Leukemia, 2009Co-Authors: Kjeld Schmiegelow, Richard M Weinshilboum, Erik Forestier, Jon Kristinsson, Stefan Soderhall, Kim Vettenranta, Finn WesenbergAbstract:Myelotoxicity during Thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme Thiopurine Methyltransferase (TPMT) and thus mo ...
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Genetic analyses of Thiopurine Methyltransferase polymorphisms in Greenlandic and Danish populations
Acta Paediatrica, 2006Co-Authors: Nina Toft, Ulrikka Nygaard, Jannie Gregers, Kjeld SchmiegelowAbstract:Aim: To determine the frequency of Thiopurine Methyltransferase (TPMT) low-activity alleles in the Greenlandic and Danish populations. Methods: 142 Greenlandic individuals and 200 Danish blood donors were screened for the TPMT G460A and A719G low-activity alleles. Results: Thiopurine Methyltransferase low-activity alleles were significantly higher in the Greenlandic compared to the Danish population, being 8.1% (95% CI 4.9–11.3) and 3.5% (95% CI 1.7–5.3) (p
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human Thiopurine Methyltransferase pharmacogenetics gene sequence polymorphisms
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Diane M Otterness, B. Klemetsdal, Jarle Aarbakke, Carol L Szumlanski, Kjeld Schmiegelow, Heiko Iven, Lynne Lennard, Jeong Ok Parkhah, Earl L Branum, John T ObrienAbstract:Thiopurine Methyltransferase (TPMT) catalyzes the S-methylation of Thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in Thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719. In the present study, we set out to determine the number, types, and frequencies of TPMT variant alleles associated with low enzyme activity in clinical laboratory samples in the United States and to compare those results with data obtained from two different ethnic groups. We identified a total of six different variant alleles for low TPMT activity in the 283 clinical laboratory samples studied. The most common variant was *3A; the second most frequent variant allele, *3C, contained only the nucleotide 719 polymorphism; and four other variant alleles were detected. TPMT*3A also appeared to be the most common variant allele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, *3C was present in samples from the Korean children, as was a novel allele, *6. Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype. Clinical Pharmacology & Therapeutics (1997) 62, 60–73; doi:
Richard M Weinshilboum - One of the best experts on this subject based on the ideXlab platform.
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Thiopurine Methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia results from the nopho all 92 study
Leukemia, 2009Co-Authors: Kjeld Schmiegelow, Richard M Weinshilboum, Erik Forestier, Jon Kristinsson, Stefan Soderhall, Kim Vettenranta, Finn WesenbergAbstract:Myelotoxicity during Thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme Thiopurine Methyltransferase (TPMT) and thus mo ...
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Thiopurine Methyltransferase activity in red blood cells of dogs
Journal of Veterinary Internal Medicine, 2004Co-Authors: Linda Kidd, Richard M Weinshilboum, Carol L Szumlanski, Oreste E. Salavaggione, Jackie L. Miller, Lauren A. TrepanierAbstract:Thiopurine Methyltransferase (TPMT) is an important enzyme in the metabolism of Thiopurine medications such as azathioprine. In humans, activity varies widely among individuals, primarily because of genetic polymorphisms. Low TPMT activity increases the risk of myelosuppression from azathioprine and 6-mercaptopurine, whereas high TPMT activity is associated with poor drug efficacy. The purpose of this study was to determine whether dogs also show a wide range of TPMT activity. Heparinized blood samples were obtained from 177 dogs associated with a veterinary teaching hospital. Red blood cell (RBC) TPMT activity was measured by means of a modification of a radiochemical method as established for use in people. TPMT activity varied across a 9-fold range (7.9–71.8 U of RBC per milliliter; median, 21.7). Variation in TPMT activity was not associated with age, sex, or neutering status. Giant Schnauzers had much lower TPMT activity (7.9–20 U of RBC per milliliter; median, 13.1; P < .001) than did other breeds, and Alaskan Malamutes had much higher TPMT activity (22.7–71.8 U of RBC per milliliter; median, 36.0; P < .001) than did other breeds. Such variations in TPMT activity in the canine population and within groups of related dogs could affect Thiopurine drug toxicity and efficacy in canine patients.
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methylation pharmacogenetics catechol o Methyltransferase Thiopurine Methyltransferase and histamine n Methyltransferase
Annual Review of Pharmacology and Toxicology, 1999Co-Authors: Richard M Weinshilboum, Diane M Otterness, Carol L SzumlanskiAbstract:▪ Abstract Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of Methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-Methyltransferase, Thiopurine Methyltransferase, and histamine N-Methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these Methyltransferase enzymes. The Thiopurine Methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of Thiopurine drugs such as 6-mercaptopurine. Phenotyping for the Thiopurine Methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical p...
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Severe Marrow Aplasia Induced by 6-Thioguanine (6TG) in a Child with Acute Lymphoblastic Leukemia (ALL) and Inherited Thiopurine Methyltransferase (TPMT) Deficiency
Pediatric Research, 1999Co-Authors: Kim L. Mcbride, Richard M Weinshilboum, W. A. Smithson, Gerald S. Gilchrist, C SzmulanskiAbstract:Severe Marrow Aplasia Induced by 6-Thioguanine (6TG) in a Child with Acute Lymphoblastic Leukemia (ALL) and Inherited Thiopurine Methyltransferase (TPMT) Deficiency
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Thiopurine Methyltransferase pharmacogenetics human gene cloning and characterization of a common polymorphism
DNA and Cell Biology, 1996Co-Authors: Carol L Szumlanski, Diane M Otterness, L Lennard, B F Brandriff, David P Kelsell, Nigel K Spurr, Eric D Wieben, Richard M WeinshilboumAbstract:ABSTRACT Thiopurine Methyltransferase (TPMT) catalyzes the S-methylation of Thiopurine drugs. Individual variation in the toxicity and therapeutic efficacy of these drugs is associated with a common genetic polymorphism that controls levels of TPMT activity and immunoreactive protein in human tissues. Because of the clinical significance of the "pharmacogenetic" regulation of this enzyme, it would be important to clone the gene for TPMT in humans and to study the molecular basis for the genetic polymorphism. As a first step toward cloning the gene for TPMT, we used the rapid amplification of genomic DNA ends to obtain a TPMT-specific intron sequence. That DNA sequence was used to design primers for the polymerase chain reaction (PCR), which made it possible to determine that the active gene for TPMT is located on human chromosome 6. A TPMT-positive cosmid clone was then isolated from a human chromosome 6-specific genomic DNA library, and the gene was sublocalized to chromosome band 6p22.3 by fluorescence ...