OVERVIEW OF PHARMACOGENOMICS
Pharmacogenomics (also known as pharmacogenetics) is a component of individualized (“personalized”) medicine that addresses how genetic factors impact drug therapy, with the goal of optimizing drug therapy and ensuring maximal efficacy with minimal side effects. The effect of drugs is traditionally divided into pharmacokinetics (how drugs are absorbed, distributed, metabolized, and eliminated) and pharmacodynamics (the molecular target or targets underlying the therapeutic effect). In principle, genetic variation can influence pharmacokinetics, pharmacodynamics, or both. Currently, most clinical applications of pharmacogenomics involve drug metabolism, but with a steady rise in applications involving pharmacodynamics. Many of the current pharmacogenomic clinical applications focus on the cytochrome P450 (CYP) enzymes. The sequencing of the human genome and intensive research into how genetic variation affects drug response hold the promise of altering the paradigms for medication therapy. However, current clinical applications using pharmacogenomics are still rather limited primarily due to limited evidence that such testing is cost effective and provides clinical benefit. The coming years should see steady growth in this field that will allow primary care providers and other health professionals to better manage drug therapy.
The most common type of genetic variation is single nucleotide polymorphism (SNP), a situation in which some individuals have one nucleotide at a given position while other individuals have another nucleotide (eg, cytosine vs adenosine, C/A). If this occurs in the coding region of a gene (ie, within coding exons), it may result in a change in the amino acid sequence that results when DNA is transcribed into RNA and the RNA is then translated into protein. Other less common types of genetic variation include insertions or deletions (sometimes referred to collectively as indels), partial or total gene deletion, alteration of mRNA splicing (ie, the process of removing introns from genomic DNA sequences that contain exons and introns), variation in gene promoters, and gene duplication or multiplication.
Genetic variants are named in a historical but often confusing system to those new to the field. By definition, the normal allele (individual copy of a gene on a chromosome) is defined as ∗1 (eg, CYP2D6∗1). In order of historical discovery, variant alleles were designated ∗2, ∗3, ∗4, and so on added later on. Unfortunately, this nomenclature does not give any clue to the nature of the genetic variation. For instance, ∗4 and ∗6 could represent fairly benign genetic variants, whereas ∗5 could signify a variant that results in complete absence of enzyme activity. However, this nomenclature is what is commonly used.
Pharmacogenomics Involving Drug Metabolism
Although numerous nongenetic factors influence the effects of medications—including disease, organ function, concomitant medications, herbal therapy, age, and gender—there are now many examples in which interindividual differences in medication response are due to variants in genes encoding drug targets, drug-metabolizing enzymes, and drug transporters. Currently, most well-established applications of pharmacogenomics involve drug ...