Introduction

As many of us can attest from personal experience, not everyone has the same response to any given medication. Some of us might find that a specific medication improves our symptoms, whereas others find that it does not. Some of us find that a given medication improves our symptoms, but we choose not to use it because it has untoward effects. The bases for such varied response to pharmacotherapies are many. Age, organ function, concomitant medications, gender, diet, and other factors all influence how individuals respond to drugs. However, genetic variation, an additional contributor to drug response, is increasingly recognized as a critical determinant of the effectiveness and safety/tolerability of pharmacological agents.

The human genome is composed of an estimated 3 billion basepairs. Of these, roughly 0.01%, or 3 million, are variable. Variability of genetic sequence takes a variety of forms, including insertions and deletions of nucleotides, but is most commonly found as single-nucleotide polymorphisms (SNPs). SNPs are distinguished from mutations based on their frequency of occurrence in the population; if the variation occurs in more than 1% of the population, it is described as a SNP, whereas a variation occurring in less 1% of the population is referred to as mutation. Many SNPs have no impact on gene function. However, some occur in coding regions and result in truncation or altered formation of the resultant gene product. SNPs occurring outside of coding regions, particularly in promoters and splice sites, can also have profound impacts on the amount or function of the resultant gene product. The study of the effects of genetic variation on drug response is known as pharmacogenetics (1-5).

Once a drug is administered, it is absorbed and distributed to its site of action, where it interacts with targets (receptors, enzymes). The drug undergoes metabolism and is then excreted. Genes that regulate each of these processes could potentially be polymorphic. By altering the amount of drug accessible to the drug target, or the nature and effects of interaction between the drug and drug target, such genetic variation can have significant clinical consequences. Clinical observations of inherited differences in drug effects were first documented some 40 yr ago when it was reported that impairment of the metabolism of a muscle relaxant by pseudo-cholinesterase was a familial trait (6). Soon after this finding was reported, it was discovered that a common genetic defect in the drug-metabolizing enzyme N-acetyltransferase could impact the plasma concentrations of a variety of drugs, including the antituberculosis agent isoniazid (7). By the early 1960s, the impact of inheritance on drug response was well recognized, and its study was termed Pharmacogenetics (8-11). Although the field has been in existence for some time, it did not become a primary area of research until the 1990s. As a result of the Human Genome Project and the advent of genomics-era technologies, pharmacogenetics has advanced tremendously.

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