Pharmacogenomics, Methods and Protocols
Kevin M. O’Shaughnessy · British Journal of Clinical Pharmacology · 2006
Pharmacogenomics, Methods and Protocols Innocenti, Federico Published by Humana Press , Totowa NJ , 2005 . 224 pages, price £59.00, ISBN 1-58829-440-4 It is almost a half-century since Friedrich Vogel coined the term pharmacogenetics, although the idea that individual response to a drug could have a genetic basis was already well established in the 1950s with, for example, the discovery of pseudocholinesterase deficiency and isoniazid acetylator status. Fifty years on, we know that most drug responses are not regulated in such an overtly Mendelian way with a single dominant gene effect. A current list of genetically determined drug responses would run to several hundreds, but it catalogues gene variants that are usually rare in the general population and have large effects on the protein they encode—often inactivating them. Deciphering the human genome has uncovered gene variation that is both commoner in the general population (usually affecting ≥ 5%) but with generally much smaller effects on protein function. This has led to the realization that most drug responses are a ‘complex’ polygenic phenomenon. Exploiting genetic polymorphisms in this way as well as using them in drug development itself has taken on the extended term of pharmacogenomics. Volume 311 of the ‘Methods in Molecular Biology’ series is an attempt to provide an introduction for would-be practitioners of this rapidly evolving subject. After a good historical overview, the methodology chapters begin with transfection assays. It focuses on a single gene (UDP-glucuronyltransferase, UGT1A1) but includes methodology that could be used generically for many genes of interest that are studied by transient or stable expression in a mammalian cell line. Single nucleotide polymorphisms, or SNPs, are the commonest genetic variation and are often probed in this way, although it would have been useful to indicate other widely used expression systems such a the Xenopus oocyte. There are then chapters addressing screening for SNP effects on RNA expression and on gene activity. Both use allele-specific probes immobilized on chips to profile the SNP effects, underlining the importance of microarrays to many high-throughput methods in pharmacogenomics. The third section addresses genotyping methods. It begins with a useful overview chapter on SNPs and other types of polymorphisms and the most appropriate methods for their detection based on the scale and scope of a genotyping project. The methodology is reasonably comprehensive, although the WAVE™ platform based on denaturing high-performance liquid chromatography is now used largely for detection and verification rather than high-throughput genotyping and there is no mention of platforms such as Ilumina™. The final section deals with the important issue of data management. This is a colossal problem of information archiving and management, but is essential to exploit fully the genomic resource we already have at our disposal. The Pharmacogenetics Resource Network and spin-off PharmGKB knowledge base are one emerging solution. The final chapter on IT systems rounds off the section, although I suspect it is fairly impenetrable to the average reader. Overall, this book provides a very useful overview of the topic of pharmacogenomics, but it is probably not comprehensive enough for the specialist. The area is driven by rapidly changing technology that will date the book relatively quickly. It also lacks discussion of important issues such as trial design and ancillary developments such as HapMap. But to be fair, it cannot be expected to be comprehensive at just over 200 pages. This book should be aimed at the expanding market of pharmacologists and clinicians coming to the area for the first time. Pharmacogenomics has already revolutionized the way we develop drugs and now looks set to make ‘personalized medicine’ a reality.