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Abstract
The combined effects of multiple polymorphisms in several drug-metabolizing enzyme and transporter genes can contribute to considerable interindividual variation in drug disposition and response. Therefore, it has been of increasing interest to generate scalable, flexible and cost-effective technologies for large-scale genotyping of the drug-metabolizing enzyme and transporter genes. However, the number of drug-metabolizing enzyme and transporter gene variants exceeds the capacity of current technologies to comprehensively assess multiple polymorphisms in a single, multiplexed assay. The Targeted Genotyping System (Affymetrix®, CA, USA) provides a solution to this challenge, by combining molecular inversion probe technology with universal microarrays to provide a method that is capable of analyzing thousands of variants in a single reaction, while remaining relatively insensitive to cross-reactivity between reaction components. This review will focus on the Targeted Genotyping System and how this technology was adapted to enable comprehensive analysis of drug-metabolizing enzyme and transporter gene polymorphisms.
Acknowledgements
The authors would like to thank David Flockhart, Richard Kim and Steven Wrighton for their assistance with defining the initial gene list; Steve Banville, Andrew Boudreau, Jim Eberle, Jay Ireland, Craig Leibelt, Aseem Mohanty, Martin Moorhead, Pragna Parmar and Farooq Siddiqui for their numerous contributions to the coding of the software and/or the molecular inversion probe design; Genaissance (now Cogenics™, a division of Clinical Data, Inc., RI, USA) for providing the ‘training‘ and ‘test‘ set samples and for the sequencing of both these sample sets; and Maneesh Jain and Nadya Oks for their helpful and critical review of this manuscript.