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Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an AnBmC architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP. Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients. Original submitted 27 July 2011; Revision submitted 24 October 2011

Aims: Population and ethnic group-specific allele frequencies of pharmacogenomic markers are poorly documented and not systematically collected in structured data repositories. We developed the Frequency of Inherited Disorders Pharmacogenomics database (FINDbase-PGx), a separate module of the FINDbase, aiming to systematically document pharmacogenomic allele frequencies in various populations and ethnic groups worldwide. Materials & methods: We critically collected and curated 214 scientific articles reporting pharmacogenomic markers allele frequencies in various populations and ethnic groups worldwide. Subsequently, in order to host the curated data, support data visualization and data mining, we developed a website application, utilizing Microsoft™ PivotViewer software. Results: Curated allelic frequency data pertaining to 144 pharmacogenomic markers across 14 genes, representing approximately 87,000 individuals from 150 populations worldwide, are currently included in FINDbase-PGx. A user-friendly query interface allows for easy data querying, based on numerous content criteria, such as population, ethnic group, geographical region, gene, drug and rare allele frequency. Conclusion: FINDbase-PGx is a comprehensive database, which, unlike other pharmacogenomic knowledgebases, fulfills the much needed requirement to systematically document pharmacogenomic allelic frequencies in various populations and ethnic groups worldwide.

Interindividual variable drug response is correlated with sequence alterations in genes encoding drug-metabolizing enzymes and transporters, affecting drug absorption, distribution, metabolism and excretion. This variable drug response may have an impact on disease therapeutic outcomes, tolerance to adverse drug reactions and even survival. Sequence alterations may occur not only within the coding region of a gene, but in its regulatory elements too, affecting gene transcription and gene-expression levels. Here, we provide a compilation of the current knowledge of pharmacogenomics related to transcription, with a focus on the effect of SNPs and short tandem repeats residing in cis-regulatory elements of 11 genes encoding for drug-metabolizing enzymes and drug transporters. In addition, we comment on two genes encoding enzymes that are drug targets themselves. Finally, we briefly discuss the currently available methodologies for clinically assessing pharmacogenomic profiles, which could potentially in the future facilitate drug treatment-individualization via the identification of molecular signatures in specific patient groups.