Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thiopurine S-methyltransferase (TPMT) genetic polymorphism has a significant clinical impact on the toxicity of thiopurine drugs. It has been proposed that the identification of patients who are at high risk for developing toxicity on the basis of genotyping could be used to individualize drug treatment. In the present study, phenotype-genotype correlation of 1214 healthy blood donors was investigated to determine the accuracy of genotyping for correct prediction of different TPMT phenotypes. In addition, the influence of gender, age, nicotine and caffeine intake was examined. TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2 and *3. Discordant cases between phenotype and genotype were systematically sequenced. A clearly defined trimodal frequency distribution of TPMT activity was found with 0.6% deficient, 9.9% intermediate and 89.5% normal to high methylators. The frequencies of the mutant alleles were 4.4% (*3A), 0.4% (*3C) and 0.2% (*2). All seven TPMT deficient subjects were homozygous or compound heterozygous carriers for these alleles. In 17 individuals with intermediate TPMT activity discordant to TPMT genotype, four novel variants were identified leading to amino acid changes (K119T, Q42E, R163H, G71R). Taking these new variants into consideration, the overall concordance rate between TPMT genetics and phenotypes was 98.4%. Specificity, sensitivity and the positive and negative predictive power of the genotyping test were estimated to be higher than 90%. Thus, the results of this study provide a solid basis to predict TPMT phenotype in a Northern European Caucasian population by molecular diagnostics.
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PMID:Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. 1522 71

Though current knowledge of pharmacogenetic factors relevant to drug metabolism is fairly comprehensive and this should facilitate translation to the clinic, there are a number of gaps in knowledge. Recent studies using both conventional and novel approaches have added to our knowledge of pharmacogenetics of drug metabolism. Genome-wide association studies have provided new insights into the major contribution of cytochromes P450 to response to therapeutic agents such as coumarin anticoagulants and clopidogrel as well as to caffeine and nicotine. Recent advances in understanding of factors affecting gene expression, both regulation by transcription factors and by microRNA and epigenetic factors, have added to understanding of variation in expression of genes such as CYP3A4 and CYP2E1. The implementation of testing for pharmacogenetic polymorphisms in prescription of selected anticancer drugs and cardiovascular agents is considered in detail, with current controversies and barriers to implementation of pharmacogenetic testing assessed. Though genotyping for thiopurine methyltransferase is now common prior to prescription of thiopurines, genotyping for other pharmacogenetic polymorphisms prior to drug prescription remains uncommon. However, it seems likely that it will become more widespread as both increased evidence that certain pharmacogenetic tests are valuable and cost-effective and more accessible genotyping methods become available.
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PMID:Genetic polymorphisms affecting drug metabolism: recent advances and clinical aspects. 2277 41