Vol 6 n° 1 - Predictors of Response to Treatment in Neuropsychiatry
Past issues Contributors How to publish Contributions and comments Home
 
hese past two decades, research on the molecu- lar mechanisms mediating the effects of pharmacologi- cal substances has been marked by enormous progress. The first important steps were the purification and iso- lation of receptor proteins, the existence of which had until then been hypothesized on the basis of their char- acteristic pharmacological effects. The next major steps were the cloning of the genes encoding these proteins1 and the discovery of a much greater multiplicity at the DNA level underlying the pharmacologically defined effects; many more receptor subtypes were found to exist at the DNA level than had originally been proposed on the basis of pharmacological classification.2 The avail- ability of the gene sequences provided the basis for pro- tein structural models. For instance, the gene family of G S t a t e   o f   t h e   a r t Genetic variation and pharmacogenomics: concepts, facts, and challenges Margret R. Hoehe, MD; Thomas Kroslak, PhD Keywords: genetic variation; DNA sequence; candidate gene; single nucleotide polymorphism; haplotype; drug response Author  affiliations:  Genetic  Variation  Program,  Department  of  Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany Address  for  correspondence:  Margret  R.  Hoehe,  MD,  Genetic  Variation Program, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany
(e-mail: hoehe@molgen.mpg.de) T The analysis of genetic variation in candidate genes is an issue of central importance in pharmacogenomics. The spe- cific approaches taken will have a critical impact on the successful identification of disease genes, the molecular cor- relates of drug response, and the establishment of meaningful relationships between genetic variants and phenotypes of biomedical and pharmaceutical importance in general. Against a historical background, this article distinguishes different approaches to candidate gene analysis, reflecting different stages in human genome research. Only recently has it become feasible to analyze genetic variation systematically at the ultimate level of resolution, ie, the DNA sequence. In this context, the importance of haplotype-based approaches to candidate gene analysis has at last been recognized; the determination of the specific combinations of variants for each of the two sequences of a gene defined as a haplotype is essential. An up-to-date summary of such maximum resolution data on the amount, nature, and struc- ture of genetic variation in candidate genes will be given. These data demonstrate abundant gene sequence and hap- lotype diversity. Numerous individually different forms of a gene may exist. This presents major challenges to the analy- sis of relationships between genetic variation, gene function, and phenotype. First solutions seem within reach. The implications of naturally occurring variation for pharmacogenomics and “personalized” medicine are now evident. Future approaches to the identification, evaluation, and prioritization of drug targets, the optimization of clinical tri- als, and the development of efficient therapies must be based on in-depth knowledge of candidate gene variation as an essential prerequisite. © 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:5-25. 5 Copyright © 2004 LLS SAS.  All rights reserved www.dialogues-cns.org