Introduction

Multiple variables influence the selection and optimization of drug therapy for each individual patient. Pharmacogenomics, the study of the influence of individual genetic variations on drug response in patients, may yield additional information to further enhance safe and effective medication use. Originally the field focused on the effects of specific variants within individual genes on drug response (i.e., pharmaco genetics), however more recent research has focused on the role of multiple variants across the genome (i.e., pharmaco genomics) and their combined potential to modify and alter drug therapy outcomes.

The understanding of pharmacogenomics has increased considerably. Most emerging research has fallen into one of three domains:

• Gene variants that influence the function of drug transporter proteins (how efficiently drugs are delivered to their site(s) of activity)
• Gene variants that cause differences in the function of drug metabolizing enzymes (how quickly or slowly drugs are utilized and broken down in the body)
• Gene variants that alter a drugs’ "target" proteins (variations in the genes coding for a target protein may alter the protein’s three-dimensional shape, changing the binding affinity for drugs to that protein)

As the biological relevance of specific genetic variants has increased, it is understood that multiple variations across the genome can contribute to significant, yet relatively predictable treatment outcomes. Virtually every therapeutic area involving medication use includes a drug for which documented genetic variability has the potential to affect drug response. Some of this information is included in the FDA-approved package insert prescribing information. For some agents, the suitability of a specific drug or the determination of an appropriate initial dose for an individual patient based on pharmacogenetic information has been incorporated into dosing algorithms and patient care. As such, it is essential that health care professionals can interpret and utilize this information to facilitate safer and more effective use of medications for individual patients.

Genetic Variation Within the Human Genome

The human genome is comprised of approximately 3 billion nucleotide base pair sequences that encode for molecular DNA with each individual having his/her own unique human genome sequence (except for identical twins). Four nucleotide bases (adenine, guanine, cytosine, and thymine) for the sequence of each single strand of DNA. Variations in nucleotide sequences can occur and contribute to alterations in the expression and activities of certain genes as well as their protein products. The location of these variations within a DNA sequence on a particular chromosome can have a profound impact on the biological activity of that gene, however it should also be understood that some gene variants may lead to little or no discernable change to biologic activity at all. As new gene variants are discovered, the process of understanding the degree of impact becomes a focus for investigators.

Proteins are involved in most enzymatic, structural, and biologic functions associated with drug disposition and effects. The processes involved in DNA replication, RNA transcription, and translation to synthesized proteins are complex. Each of these processes is potentially susceptible to consequences of DNA sequence variations.

Genetic variations can take many forms, but most fall into three general categories:

• single nucleotide base substitutions (e.g., a cytosine substituted for an adenine)
• insertions or deletions of a nucleotide base within a sequence
• deletions or extra copies of entire DNA sequences (e.g., trisomy 21, in which an extra copy of all genes on the 21st chromosome are present)

Variations in DNA that occur at a frequency of greater than 1% in the population are called polymorphisms. The most common gene varients in humans are single nucleotide polymorphisms (SNPs, pronounced as the word "snips" in dialogue). SNPs result from the substitution of one nucleotide base for another. The location of a SNP within a gene is important, as the location may or may not elicit a downstream effect on protein made from the gene. It is helpful to recall the importance of introns and exons for mRNA manufacturing when considering how SNPs can impact protein function. An important point to keep in mind is that any gene variant may have a spectrum-like impact on protein manufacture ranging from zero clinical consequences (no discernible effect on proteins) to complete lack of functional proteins associated with significant alterations in drug response. Also, pharmacogenomic clinical effects must always be considered within the larger sphere of environmental influences on drugs and drug responses. Finally, due to the commonality of polymorphisms, multiple gene variants may be present within one patient, making prediction of drug response particularly challenging.

Clinical Significance of Genetic Polymorphisms

SNPs and other genetic variations influence drug response at different levels through alterations in the activities of enzymes or proteins involved in drug absorption, transport, metabolism, elimination, or at the drug target receptor (site of drug action). Clinically relevant polymorphisms have been identified for genes that encode for most of the common enzymes involved in drug metabolism. Most enzymes are localized intracellularly throughout a wide variety of tissues in the body, including the enterocytes that line the intestine and within hepatocytes. Variants that cause diminished or absent enzyme activity decrease drug metabolism processes. In this case, if the drug is metabolized to an inactive product, then the prolonged persistence of the parent drug in the body could result in excessive pharmacologic effects and potential toxicities may occur. If the drug requires enzymatic conversion to a pharmacologically active metabolite, drug response may be reduced or absent. In contrast, if the variation is due to extra copies of a gene that results in increased enzymatic activity, opposite effects on drug metabolism and response can occur.

Similar outcomes can be associated with polymorphisms in genes that encode for membrane transporter proteins that are responsible for drug transport into cells (influx), as well as proteins that participate in energy-dependent processes that export drugs out of cells (efflux transporters). Polymorphisms in drug transport proteins can influence drug response by altering drug gastrointestinal absorption, uptake and distribution in tissues, exposure to intracellular drug metabolizing enzymes, and elimination via the bile or urine. Finally, some genes that encode for certain drug receptors are highly polymorphic, resulting in attenuated or exaggerated drug responses. The number of polymorphic genes responsible for variations in drug response at drug receptors is relatively small compared to those associated with drug metabolizing enzymes or transport proteins; however, this area has undergone the least amount of study to date.

Incorporating Pharmacogenomic Information into Clinical Practice

Most drugs are initiated in individual patients based on knowledge about their safety and effectiveness within the general population. Information regarding patient characteristics (e.g., age, ethnicity, renal/hepatic function, concomitant disease, etc.) known to contribute to variability in drug response, when available, is considered at this time. It is becoming more and more common, however, to consider gene variants as well when initiating drugs, as interindividual gene factors are thought to contribute to drug response variability in 15-30% of patients. Currently, there are more than 122 with pharmacogenomic information included in the package insert. For selected agents, dosing recommendations based on an individual’s genetic information (i.e., genotype) for specific drugs and drug classes are also considered. Genomic biomarkers can play an important role in identifying responders and non-responders, avoiding drug toxicity, and adjusting the dose of drugs to optimize their efficacy and safety. However, the typical strategy for most drug therapy is to monitor the patient’s response to treatment and modify regimens as necessary. Patients who develop exaggerated pharmacologic responses or elicit no pharmacologic effect may be expressing a phenotype suggestive of altered drug disposition or target receptor effect that could be associated with an underlying genetic polymorphism. As we continue to learn more about these associations and can incorporate pharmacogenomic information into decisions regarding drug therapy for individual patients, the ultimate goal is to improve therapeutic outcomes by limiting drug exposure to patients that are most likely to derive no therapeutic benefit and/or experience toxic drug effects.

For example, some genetic variants are associated with hypersensitivity reactions to a specific drug. A prescriber who is contemplating initiating that drug for a patient may need to determine whether the patient possesses that variant in their DNA. If that specific variant is present, the prescriber might select an alternate agent, thereby avoiding a potentially life-threatening hypersensitivity reaction. In another example, patients who are determined to have a genetic variant that results in an inactive metabolizing enzyme would not be appropriate candidates for an analgesic drug that requires that enzyme to convert the drug to the active analgesia-producing form. On the other hand, if that metabolizing enzyme is responsible for conversion of an active parent drug to an inactive metabolite, the starting dose of the drug may be reduced or perhaps an alternate drug might be selected.

Several Clinical Laboratory Improvement Amendment (CLIA)-approved laboratories offer pharmacogenetic testing to identify relevant genetic polymorphisms that predict drug response and can be used to initiate appropriate drugs and dosing regimens for individual patients. Some of these tests, while recommended in drug prescribing information, are costly and may not be covered by insurance. Patients may not fully understand the utility of undergoing genetic testing and providing a specimen for DNA analysis, which is typically performed on a blood, saliva, buccal swab, or other tissue collection. On the other hand, patients who are engaged in their medical care may be familiar with the concept of "personalized medicine" and seek information about available tests to "individualize" their own drug therapy. Many drugs are now required to have pharmacogenetic testing performed before they are prescribed. Other drugs have labeling that includes "test recommended" or "for information only." Health care professionals will need to be familiar with pharmacogenetic tests that are recommended for specific drug therapies, how to interpret the results of those tests, and how to incorporate pharmacogenetic data with other clinical information to optimize patient drug therapy and health care outcomes.

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