Polymorphisms affecting gene regulation and mRNA processing: broad implications for pharmacogenetics.
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.
Johnson
Andrew D
AD
Integrated Biomedical Sciences Graduate Program, Department of Pharmacology, College of Medicine and Public Health, The Ohio State University, 5072 Graves Hall, 333 W. 10th Avenue, Columbus, OH 43210-1239, USA. johnson.2060@osu.edu
Wang
Danxin
D
Sadee
Wolfgang
W
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001711:Biotransformation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System