Van Eyk, Dunn - Proteomic and Genomic Analysis of Cardiovascular Disease - 2003 (522919), страница 97
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Accordingly, not only the differencesin the magnitude of beneficial response to therapy but also the frequency and severityof side effects and drug-drug interactions are partly determined by SNPs that affectdrug metabolism, such as those located in cytochrome p450 genes.20.3 Genomics and the Process of Drug DiscoverySNPs in target proteins, by affecting the sensitivity of the target to drugs (pharmacodynamics), are also major determinants of response to drug therapy. SNPsin CETP have been implicated in response to pravastatin [87] and an insertion/deletion polymorphism in the ACE-1 gene has been associated with response totreatment with ACE-1 inhibitors [88].
SNPs and haplotypes in human ether a gogo-related (HERG) and KCNH2 (formerly known as Mirp1) have been associatedwith drug-induced long QT syndrome and torsade de pointes [89], those in b2adrenergic receptors with progression of heart failure [90], vascular responsiveness[91] and response to bronchodilators [92], and those in ryanodine receptor 2 withanesthesia induced malignant hyperthermia [93, 94].The ultimate goal of drug therapy is to develop drugs that are targeted to a specific phenotype and provide maximum beneficial effects with minimal side effects. Pharmacogenomic and pharmacogenetic research could provide the opportunity to identify new drug targets, design drugs more selective to the phenotypeand to individualize drug therapy.
Major strides have already been made and advances in genomics will accelerate the pace of our progress toward achievingthese goals.Tab. 20.1 Genomics-based approach to drug discovery and therapyTarget identification (gene mapping and expression profiling)Identifying the causal gene (single gene disorders)Identifying the susceptibility genes (complex traits)Identifying the modifier genesIdentification of differentially expressed mRNAIdentification of differentially expressed proteinsTarget validation (functional genomics)Cell culture studiesTransgenesisGene targeting studiesGene transferLead identification (Structural genomics)Determining 3-dimensional structure of proteinsIdentification of protein-protein interactionLead validation (Gene based therapy)Cell culture studiesTransgenesisGene targetingGene transfer and other gene therapy approachesGenomics and individualized drug therapySNP and haplotype association studies35335420 Genomics Perspective for Drug Discovery20.4AcknowledgementsThis work is supported in part by grants from the National Heart, Lung, andBlood Institute, Specialized Centers of Research P50-HL42267-01 and 1R01HL/DK68884-01.20.5References134567891011Drews, J.
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