Ann M. Moyer, MD, PhD
Ann M. Moyer, MD, PhD, Associate Professor of Laboratory Medicine and Pathology and an Assistant Professor of Pharmacology, Mayo Clinic, Rochester, Minn.
Every person has a unique set of genes, and these genes can influence how their body processes and reacts to different drugs. Tiny genetic differences can mean the difference between a drug working as intended or being either too strong or too weak. They can affect how people experience side effects and even toxicity.
Pharmacogenomics, the study of these interactions, can be applicable to many drugs, but some medications are more likely to be influenced by a person’s genetic makeup than others.
Antidepressants. Studies have identified genetic variants that can affect how a person responds to antidepressant medications. Genetic variants can affect the enzymes involved in drug metabolism, neurotransmitter transporters and receptors, and other molecular targets that affect how antidepressants work in the brain. Changes in the cytochrome P450 enzyme system can affect the rate at which a particular medication is broken down in the body.
Cancer drugs. Not all patients with the same type of cancer respond to treatment in the same way. Some patients have genetic variations that affect how their bodies break down and eliminate chemotherapy drugs, which can impact the effectiveness and toxicity of treatment. By testing for these variations, doctors can adjust the dose or type of chemotherapy drug used to better match the patient’s individual metabolic profile, potentially improving the chances of a positive treatment outcome while minimizing side effects. For example, a UGT1A1 genotyping test identifies genetic variants that impact the activity of UGT1A1 enzyme, which metabolizes irinotecan, a chemotherapy drug used to treat colorectal cancer. Variations in this gene can increase the risk of severe side effects, such as neutropenia and diarrhea.
Pharmacogenomics can also be used to develop therapies that are designed to target specific molecular abnormalities in cancer cells. (While we use the term pharmacogenomics here, some people use the term pharmacogenomics only to refer to inherited genetic variations in all of a patient’s cells, not just the variants that are acquired in only the tumor cells.) These drugs are often more effective and have fewer side effects than traditional chemotherapy, but they work only for patients whose cancer cells have the specific molecular target that the drug is designed to inhibit.
Pain medications. Nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen and diclofenac, block the production of certain enzymes that cause pain and inflammation. Genetic variations in the CYP2C9 gene can affect the metabolism of NSAIDs, leading to slower clearance of the drugs from the body. This can increase the risk of side effects such as gastrointestinal bleeding, especially in older patients.
Proton-pump inhibitors. Genetic variations in the CYP2C19 gene can affect the metabolism of PPIs such as omeprazole, esomeprazole, and lansoprazole. People with a reduced-function CYP2C19 genotype may metabolize these drugs more slowly. The reduced-function CYP2C19 genotype is more common in Asian and African populations than in European populations. On the other hand, individuals with a rapid metabolizer genotype may metabolize these drugs more quickly, leading to lower drug levels in the blood and potentially reduced efficacy.
Thiopurines. An enzyme called thiopurine S-methyltransferase (TPMT) helps the body process drugs that are commonly used to treat conditions such as leukemia, inflammatory bowel disease, and autoimmune disorders. If a person who is deficient in TPMT takes a thiopurine medication, the drug can build up and cause bone marrow damage and other side effects. Depending on your ancestral background, you may be less likely to have a TPMT variant, but instead have a variant in NUDT15. In the mid-2010s, studies revealed that, in some populations in which TPMT variants are less common, NUDT15 variants are more common and have a similar impact with regard to thiopurines. But a genetic test can prevent these effects by alerting the prescribing physician before it’s too late.
As exciting as pharmacogenomics is, there are limitations. While scientists have identified many genes that influence drug metabolism and response, there are still many more genes and interactions to be discovered. As a result, there may be cases in which pharmacogenomic testing doesn’t provide clear guidance for medication selection or dosage. Furthermore, while pharmacogenomics can help identify which medications are likely to be most effective for a particular patient, for a lot of drugs, scientists don’t know what role genetics plays or what genes may be involved. They’re more using a patient’s genetics to rule a drug in or out, not to select the perfect drug. This can limit the practical applications of pharmacogenomics in some cases.
Finally, pharmacogenomics testing can be expensive, and insurance may not always cover the cost. If your doctors offers a test, make sure you investigate your coverage.
Several companies offer pharmacogenomic tests directly to patients. If you try these companies’ tests, be sure to discuss the results with your physician before stopping any medications.
Your health-care provider may also offer you a test from an academic medical center, such as Mayo Clinic, or a for-profit company.
If you choose to undergo testing, it’s important to discuss the results with your health-care provider before making any drug changes. For example, you may get a report that notes a specific SSRI you already take can be less effective in people with your genetic make-up. But if it’s working for you—and your doctor has already worked with you to get the dosage just right—there’s no need to make a change. If, however, you’re having a lot of side effects from a drug you take, a genetic test could help your physician choose a better alternative. Either way, the science is more complex than the report you may receive, and it requires professional input to best interpret.
