Polymorphisms affecting gene regulation and mRNA processing: Broad implications for pharmacogenetics

  • Johnson A
  • Wang D
  • Sadee W
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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. © 2004 Elsevier Inc. All rights reserved.

Author-supplied keywords

  • Allele-specific
  • Cis-Regulatory
  • Cytochrome
  • Genotype-phenotype
  • Pharmacogenetics
  • Pharmacogenomics
  • Polymorphism
  • RNA
  • Review
  • SNP

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Authors

  • Andrew D. Johnson

  • Danxin Wang

  • Wolfgang Sadee

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