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Abstract
Aim: Many studies focus on monitoring response to chemotherapy, adverse effects and prediction of therapeutic effects, which depend on individual gene variability. The amount of various polymorphisms in genes involved in the folate cycle, and other metabolic pathways involved in the metabolism of chemotherapeutic drugs, are an essential topic of such studies. This work focuses on the design and establishment of a pharmacogenetically relevant panel, which could be applied to the rapid genotyping of patients treated with thiopurines, 5-fluorouracil, methotrexate, irinotecan and glucocorticoids. Materials & methods: A total of 97 variations in 36 genes associated with side effects of chemotherapeutic treatment were selected. Of these, 94 SNPs were genotyped by the arrayed primer extension (APEX; Asper Biotech Ltd) microarray method or direct sequencing. Variations of tandem repeats or gene deletions were genotyped by capillary electrophoresis and PCR detection. A total of 300 DNA samples from healthy volunteers were tested to estimate genotype frequencies for a Slovak population. All data were checked for Hardy–Weinberg equilibrium and genetic linkage between variations. Results: We designed an APEX microarray for genotyping pharmacologically relevant polymorphisms in patients undergoing chemotherapy. We estimated genotype frequencies for all 97 polymorphisms testing 300 individuals from the Slovak population, which may also serve as an estimate of central European frequencies. These data also allowed for the testing of genetic linkage between loci. Many of the determined genotype frequencies in this study were in similar ranges found in other European populations but four SNPs, rs11760837 (p = 0.018), rs1801265 (p = 0.0375), rs1801394 (p = 0.0066) and rs182455 (p = 0.0083), demonstrated stronger deviation. Conclusion: Genetic variability in genes involved in metabolic pathways of chemotherapeutic drugs, such as methotrexate, 5-fluorouracil, thiopurines or irinotecan, is responsible for individual therapy response and development of side effects. A comprehensive approach in genotyping of numerous variants is aimed to improve individual access to patients and the selection of appropriate drugs for treatment. The APEX microarray method is a valuable tool for fast, reliable and cost-effective genotyping of variants which can be used for the typing of known variants in patients prior to treatment as well as in studies searching for new genotype–phenotype associations. The opportunity of adding additional variants during the study makes the APEX microarray technology flexible and suitable for such trials.
Original submitted 4 October 2010; Revision submitted 23 November 2010.
Financial & competing interests disclosure
This study was supported by grant number MZ 2007/42-UK-18 from the Ministry of Health of the Slovak Republic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.