Technologies for detecting genetic polymorphisms in pharmacogenomics

Background: Pharmacogenomics is an emerging scientific discipline examining the genetic basis for individual variations in response to therapeutics. Methods and Results: Genetic polymorphisms are a major cause of individual differences in drug response, Metabolic phenotyping can be accomplished by administrating a probe drug or substrate and measuring the metabolites and clinical outcomes. However, this approach tends to be labor intensive and r equires repeated sample collection from the individual being tested. Altern atively, genotyping allows determination of individual DNA sequence differe nces for a particular trait. Commonly used genotyping methods include gel e lectrophoresis-based techniques, such as polymerase chain reaction (PCR) co upled with restriction fragment length polymorphism analysis, multiplex PCR , and allele-specific amplification. Fluorescent dye-based high-throughput genotyping procedures are increasing in popularity, including oligonucleoti de ligation assay, direct heterozygote sequencing, and TaqMan (Perkin Elmer , Foster City, CA) allelic discrimination. High-density chip array and mass spectrometry technologies are the newest advances in the genotyping field, but their wide application is yet to be developed. Novel mutations/polymor phisms also can be identified by conformation-based mutation screening and direct high-throughput heterozygote sequencing. Conclusions: Rapid and accurate detection of genetic polymorphisms has grea t potential for application to drug development, animal toxicity studies, i mprovement of human clinical trials, and postmarket monitoring surveillance for drug efficacy and toxicity.