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The study of pharmacogenomics addresses the interactions of multiple genes and gene products and their impact on drug therapy, with the goal of developing rational means to optimize drug therapy and ensure maximal efficacy with minimal side effects. In a gross way physicians already use pharmacogenomics when choosing cardiac drugs for patients. For example, hypertensive patients of African background and black race tend to respond better to diuretics and worse to angiotensin-converting enzyme inhibitors and β-blockers. A study investigating congestive heart failure in blacks was terminated prematurely because of an absolute risk reduction in the death rate of 4%. The Food and Drug Administration (FDA) then approved the combination of two well-known drugs, isosorbide and hydralazine, as an adjunct to standard treatment of heart failure in African Americans.

In practice, however, humans and their genome are much more complicated than a simple classification based on race. For example, hypertension in African Americans is higher than that in Caucasian Americans, but the same among African Cubans and Caucasian Cubans. Furthermore, studies of human genetic diversity often sample small numbers of members of a racial or ethnic group, and importantly, membership in a particular ethnic group or race is often defined more by the subject's ethnic identification than by objective criteria. In addition, genetic studies are not usually designed to assess other important influences on medical phenomena such as environment, social class, poverty, and lifestyle. Using race to guide prescription of medication is a proxy for understanding the underlying genetic, environmental, social, economic, and lifestyle causes of illness.

The effect of drugs is traditionally divided into pharmacokinetics (how drugs are absorbed, distributed, metabolized, and eliminated) and pharmacodynamics (target or targets underlying the therapeutic effect). In principle, genetic variation can influence either pharmacokinetics or pharmacodynamics, or both. Currently, most clinical application of pharmacogenetics involves pharmacokinetics, but over time more attention will shift to pharmacodynamics. The sequencing of the human genome and intensive research into how genetic variation affects drug response holds the promise of altering the paradigms for medication therapy. However, as will be discussed later, current clinical applications utilizing pharmacogenetics are still rather limited. 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.

Evans WE, Relling MV: Moving towards individualized medicine with pharmacogenomics. Nature 2004;429:464-468.  [PubMed: 15165072]
Goldstein DB et al: Pharmacogenetics goes genomic. Nat Rev Genet 2003;4:937-947.  [PubMed: 14631354]
Weinshilboum R, Wang L: Pharmacogenomics: Bench to bedside. Nat Rev Drug Discov 3:739-748.  [PubMed: 15340384]

Genetic Variability

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 versus adenosine, C/A). If this occurs in the coding region of a gene (ie, within coding exons), this ...

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