Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9016141 | Pharmacology & Therapeutics | 2005 | 20 Pages |
Abstract
Functional polymorphisms that alter gene expression and mRNA processing appear to play a critical role in shaping human phenotypic variability. Intensive studies on polymorphisms affecting drug response have revealed multiple modes of altered gene function, frequently involving cis-acting regulatory sequence variants. Experimental and in silico methods have advanced the search for such polymorphisms, but considerable challenges remain. Here, a survey of polymorphisms in drug-related genes indicates that: (a) a substantial proportion of genetic variability still remains unaccounted for; (b) a majority of these genes harbors known regulatory polymorphisms; and (c) a portion of polymorphisms affect splicing and mRNA turnover. Pharmacogenetic optimiziation of individual drug therapy may require a complete understanding of all functional sequence variants in key genes. This review surveys known noncoding polymorphisms in genes encoding cytochrome P450s and other drug-metabolizing enzymes, drug transporters, and drug targets and receptors. Current methods and challenges associated with the identification and characterization of functional polymorphisms are also discussed.
Keywords
VDRhnRNATYMSCREATEOATPPPAR-αPXRTPMTESESULTIVSHTR2A6-MercaptopurineDRD25-HTTLPRPTCVNTRUSF1UTRPharmGKBheterogeneous nuclear RNASLCOcancer genome anatomy projectCGAPnuclear transcription factor YTSERFXRABCBCCAAT/enhancer binding proteinsNF-YCis-regulatoryDPYD6-thioguanine6-TG5-HTTDBPSIFTCyPADHMALDI-TOFACENATPGAETsHMGCR5-FUCRMMMPALDHSLC3-Hydroxy-3-Methylglutaryl-coenzyme A reductase6-MPC/EBPHnfN-acetyltransferaseSp-1aldehyde dehydrogenaseperoxisome proliferator-activated receptor alphaAllele-specificRNAPara-aminobenzoic acidexonic splicing enhancerAlcohol dehydrogenasevariable number tandem repeatbase pairsolute carrierdihydropyrimidine dehydrogenasebinding siteserotonin transporterthymidylate synthasecytochromehepatocyte nuclear factorPharmacogeneticsPharmacogenomicsSp1 transcription factor5-fluorouracilhepatic lipaseLipcLow-density lipoproteinLDLmatrix metalloproteinaseCARCis-regulatory moduleintermediate metabolizerextensive metabolizerpoor metabolizerReviewAREPABAorganic anion-transporting polypeptidePolymorphismSingle nucleotide polymorphismSNPGenotype-phenotypepremature termination codonkilobasesconstitutive androstane receptordopamine D2 receptorVitamin D receptorPregnane X receptor
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Authors
Andrew D. Johnson, Danxin Wang, Wolfgang Sadee,