Overview: What is pharmacogenetics?
Some of us respond differently than others to the same medications that we take, or we may experience different side effects from drugs. The way we respond can be due to the genes we have inherited. With respect to drugs, our unique genetic make-up and our individual response may mean that a drug that is effective for one person may be less effective for another or that a drug that is safe for one person may be less safe for another person—even at the same dosage. Photo source: NHGRI, Ernesto del Aguila III
Most drugs are broken down (metabolized) in the body by various enzymes. In some cases, an active drug is made inactive (or less active) through metabolism. In other cases, an inactive (or less active) drug is made more active through metabolism. The challenge in drug therapy is to make sure that the active form of a drug stays around long enough to do its job. However, some people have variable enzyme action so that they may metabolize the drug too quickly or too slowly or not at all — meaning that the drug may not produce its intended effect or it may remain in a person's system too long and may lead to side effects.
Individual response to a drug may also be related to variability in the drug target, for example a protein that the drug binds to in order to produce its specific effect. Furthermore, individuals may experience side effects (known as hypersensitivity reactions) from certain medications due to variability in proteins involved in the immune response.
Pharmacogenetics is the study of genetic variability that causes individual responses to medications. By analyzing the genes that produce the specific drug targets or enzymes that metabolize a medication or are associated with immune response, a healthcare practitioner may decide to raise or lower the dose or even change to a different drug. The decision about which drug to prescribe may also be influenced by other drugs the person is taking in order to avoid drug-drug interactions.
The terms "pharmacogenetics" and "pharmacogenomics" are sometimes used interchangeably. There are subtle differences in the meaning of the two terms and there is no consensus on the exact definitions. In general, pharmacogenomics refers to the overall study of the many various genes that contribute to drug response. Pharmacogenetics is the study and evaluation of the inherited differences (genetic variations) that affect drug metabolism and an individual's response to medications. For the purposes of this article, the term pharmacogenetics will be used.
Why is pharmacogenetics important?
When initiating drug therapy to treat a particular condition, healthcare practitioners typically prescribe one of several appropriate drugs. Dosages and timing of drugs are usually based upon the anticipated rate of metabolism and clearance from the body in the average person. They prescribe a "standard" dose based on factors such as weight, sex, and age. Clinically, however, each person responds uniquely to treatment and healthcare practitioners must make adjustments. For example, the healthcare practitioner may adjust the drug dose or switch to a different therapy, depending on whether the person's condition is responding to the medication and whether the individual is experiencing unpleasant or dangerous side effects. Sometimes a person may find that a treatment that has been working well suddenly causes symptoms when that person starts taking an additional drug.
The concentrations or effects of some drugs are monitored with blood tests and the drug dosages may be increased or decreased to maintain the drug level in an established therapeutic range. Follow-up of drug concentration is called therapeutic drug monitoring. If changing the drug dose is not effective in treating or controlling the person's condition, or the person still has side effects, then the person may be given a different drug.
In contrast, pharmacogenetics offers healthcare providers the opportunity to individualize drug therapy for people based on their genetic make-up. Testing people prior to initiating drug therapy to determine their likely response to different classes of drugs is a key emerging area of testing. Such genetic information could prove useful to both the healthcare practitioner and patient when choosing current and future drug therapies and drug doses. For certain medications, pharmacogenetics is already helping healthcare providers predetermine proper therapies and dosages to have a better chance of achieving the desired therapeutic effect while reducing the likelihood of adverse effects.
How do genes vary and how does pharmacogenetic testing work?
Genes are the basic units of genetic material, the segments of DNA that usually code for the production of specific proteins, including the proteins known as enzymes. Each person has two copies of most genes: one copy is inherited from the person's mother and one copy is inherited from the person's father. Each gene is made up of a specific genetic code, which is a sequence of nucleotides (A, T, G, or C). For each nucleotide position in the gene, one of the four nucleotides is the predominant nucleotide in the general population. This nucleotide is usually referred to as "wild type." If an individual has a nucleotide that is different from "wild type" in one copy of his or her genes, that person is said to have a heterozygous variant. If an individual has the same variant nucleotide in both copies of his or her genes, that person is said to have a homozygous variant.
Nucleotide or genetic variants (also called polymorphisms or mutations) occur throughout the population. Some genetic variants are benign — do not produce any known negative effect or may be associated with features like height, hair color, and eye color. Other genetic variants may be known to cause specific diseases. Other variants may be associated with variable response to specific medications.
Pharmacogenetic tests look for genetic variants that are associated with variable response to specific medications. These variants occur in genes that code for drug-metabolizing enzymes, drug targets, or proteins involved in immune response. Pharmacogenetic tests have the ability to determine if a variant is heterozygous or homozygous, which can impact an individual's response or reaction to a drug.
When are the tests ordered?
A healthcare practitioner may test a patient's genes for certain variations that are known to be involved in variable response to a medication at any time during treatment (for example, prior to treatment, during initial phase of treatment, or later in the treatment). The results of the testing may be combined with the individual's clinical information, including age, weight, health and other drugs that they are taking, to help tailor therapy. Sometimes, the healthcare practitioner may use this information to adjust the medication dose or sometimes to choose a different drug. Pharmacogenetic testing is intended to give the healthcare practitioner additional information but may not replace the need for therapeutic drug monitoring.
Pharmacogenetic testing for a specific gene is only performed once since a person's genetic makeup does not change over time. Depending on the medication, a single gene may be ordered or multiple genes may be ordered. An example of a medication for which multiple genes are usually evaluated is warfarin, which can be affected by genetic variation in CYP2C9 and VKORC1.
Testing may be ordered prior to starting specific drug therapies or if a person who has started taking a drug is experiencing side effects or having trouble establishing and/or maintaining a stable dose. Sometimes a person may not experience such issues until other medications that affect the metabolism or action of the drug in question are added or discontinued.
The Pharmacogenetic Tests
Pharmacogenetic testing is available for a relatively limited number of drugs. Some tests may only be applicable to specific ethnic groups. The following are examples of some drugs for which pharmacogenetic tests are available:
|Drug||Associated Diseases/Conditions||Gene(s) Tested|
|Warfarin (see Warfarin Sensitivity Testing)||Excessive clotting disorder||VKORC1 and CYP2C9|
|Thiopurines (azathioprine, mercaptopurine, and thioguanine) (see TPMT)||Autoimmune/Childhood leukemia||TPMT|
|Clopidogrel (see Clopidogrel (CYP2C19 Genotyping))||Cardiovascular||CYP2C19|
|Some antidepressants, some antiepileptics (e.g., phenytoin, phenobarbital, carbamazepine, valproic acid)||Psychiatric, Epilepsy||CYP2D6, CYP2C9, CYP2C19, CYP1A2, SLC6A4,HTR2A/C|
|Some antipsychotics (e.g., haloperidol, mephobarbital, thioridazine)||Psychiatric||DRD3, CYP2D6, CYP2C19, CYP1A2|
|Methylphenidate||Attention deficit disorder||DRD4|
|5-fluorouracil||Cancer||DPYD variants and TYMS gene mutations testing|
|Selective serotonin reuptake inhibitors (SSRIs)||Depression||5-HTT|
|Some statins (e.g., simvastatin)||High cholesterol||SLCO1B1|
Is there anything else I should know?
Pharmacogenetic testing is available for a relatively limited number of medications. Pharmacogenetics tests are generally not widely used and not all insurers will cover their cost. Individuals should consult with their healthcare practitioners about these issues.
Pharmacogenetic tests are intended to provide the healthcare practitioner and patient with additional information when selecting drug treatments and dosages. For a better understanding, patients may want to consult with a genetic counselor prior to and after having a pharmacogenetic test performed. Genetic counseling and informed consent are recommended for all genetic testing.
To learn more about the role of pharmacogenetics in personalized medicine, visit the Personalized Medicine Coalition website.
1. Should everyone have pharmacogenetic tests performed? Currently they are only indicated if a person is going to take, or is taking, a drug that has an accepted pharmacogenetic test associated with it.
2. Is pharmacogenetic testing required before taking certain drugs? No. The FDA may recommend this testing, as in the case of irinotecan, but it is not required.
3. Why am I only tested once? Your genetic make-up does not change over time. You may, however, have other pharmacogenetic tests performed if you take a different drug with a different associated pharmacogenetic test.
4. Does this mean my drug levels do not have to be monitored? No. Since there are other factors that affect drug levels besides your genetics, therapeutic drug monitoring may still be necessary.
5. What type of sample is used? A blood sample is obtained by inserting a needle into a vein in the arm. Saliva samples and buccal swabs, collected by brushing the inner side of the cheek with a swab, can also be used.
6. How do pharmacogenetic tests differ from genetic tests? Pharmacogenetic tests are performed to evaluate a person's potential response to a drug therapy. Most genetic tests have been developed to help diagnose or predict the development of a genetic disease, for forensic medicine purposes, and in establishing parentage. Another common use of genetic testing is to detect the genetic material (DNA or RNA) of bacteria and viruses to help diagnose an infection. (Read the article The Universe of Genetic Testing for more information.)
7. Will I be monitored differently after the test? You may be monitored differently depending on the results of the test, especially when starting the medication, changing the dose, or when adding or discontinuing another medication.
8. Should family members be tested? This is a question to discuss with your healthcare provider and your family members. In some cases it may be useful; in others it may only be relevant if they are going to be taking the same drug or a drug in the same class. Pharmacogenetic test results are useful information for a family member to share with the healthcare practitioner along with the family's medical history.
9. How do I know whether or not I should have testing done? You and your healthcare provider should consider the condition that you have, your history of drug-related side effects and/or adverse drug reactions, the drug therapies that are available, and the uses the test is intended for. Pharmacogenetic tests are not meant to stand alone but are meant to be used in conjunction with your other clinical findings.
Elsewhere on the Web
Association for Molecular Pathology
National Institutes of Health: Medicines for You
Genetics Home Reference: What is pharmacogenomics?
University of Utah Health Sciences: Pharmacogenomics Interactive Tutorial
Personalized Medicine Coalition
Mayo Clinic: Personalized medicine and pharmacogenomics
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Linnea Baudhuin, Phd, DABMG. Assistant Professor of Laboratory Medicine. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.