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Pharmacogenetics
Pharmacogenetics (PGx) is the study of how differences in our genetic make-up affect each person's response to a certain medication. Currently, PGx testing at SickKids is only available through a research project study called the Clinical Pharmacogenetics Research Pilot Study, or CPS Pilot. Through this pilot study, PGx testing allows us to provide individualized patient care for patients prescribed medications for certain conditions including:
- pain management,
- mental health,
- cardiology,
- gastroenterology,
- infectious diseases,
- oncology,
- autoimmune disorders and
- neurological disorders.
What is pharmacogenetics?
Pharmacogenetics is the study of how differences in our genetic make-up affect each person's response to a certain medication. It can help predict how a person will process a medication and provides caution about potential side effects.
Which genes are currently tested at SickKids?
Referred patients will be tested for a multi–gene panel consisting of genetic variants which can be used in the clinical setting. These variants are known to affect responses to certain medication therapies or risk of side effects. All of the variants on the PGx panel have published clinical practice guidelines* available. Medications that may be impacted by PGx variants are in the areas of pain management, mental health, cardiology, gastroenterology, infectious diseases, oncology, autoimmune disorders and neurological disorders.
*Clinical practice guidelines are published by the following organizations: CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: Dutch Pharmacogenetics Working Group; CPNDS: Canadian Pharmacogenomics Network for Drug Safety; FDA: U.S. Food and Drug Administration
What effect can each gene variant predict on medication response?
Browse the sections below to learn about the clinically-relevant genes currently being tested for at SickKids and how they contribute to medication metabolism, medication transport and how their variants effect their function.
If you require the information listed below in an alternative format, please submit the Alternate Format Request Form.
Cytochrome P450 (CYP) enzymes are medication-metabolizing enzymes and are responsible for breaking down or activating many commonly used medications. Genetic variations in the CYP450 genes can lead to an increase or decrease in enzyme activity. This can alter the amount of medication available in the body and may potentially impact medication response.
The PGx test at SickKids will predict the enzyme activity of CYP2D6, CYP2C19, CYP2C9, CYP2B6 and CYP3A5. Enzyme activity can be grouped into different categories.
Metabolizer activity and effect on medication response of CYP2D6, CYP2C19 CYP2C9 AND CYP2B6:
| Metabolizer activity | Effect on Medication Response |
|---|---|
| Poor Metabolizer (PM) - lack of enzyme activity | Little to no enzyme activity can lead to increased risk of side effects due to reduced medication elimination OR lack of medication effectiveness, resulting from failure to produce the active form of the medication. |
| Intermediate Metabolizer (IM) - reduced enzyme activity | Reduced enzyme activity can lead to reduced elimination of the medication and increased probability of side effects. |
| Normal Metabolizer (NM) - normal enzyme activity | Average enzyme activity and normal medication performance based upon medication label specifications. This is the most common metabolizer activity. |
| Rapid (fast) Metabolizer (RM) – increased enzyme activity (For CYP2C19 only) |
Higher than average enzyme activity can lead to reduced medication effectiveness OR increased risk of side effects due to increased exposure to active medication metabolites |
| Ultrarapid (very fast) Metabolizer (UM) – increased enzyme activity | Higher than average enzyme activity can lead to reduced medication effectiveness OR increased risk of side effects due to increased exposure to active medication metabolites. |
CYP3A5 enzyme activity can help further predict how this enzyme is expressed by an individual.
Expression activity and effect on medication response of CYP3A5:
| Expression Activity | Effect on Medication Response |
|---|---|
| CYP3A5 non-expressor (poor metabolizer) | Individuals who are CYP3A5 non-expressors have little to no enzyme activity and are recommended to begin medication therapy using standard dosing guidelines. This is because medications are often developed for the average population. In the case of CYP3A5, this level of expression activity represents the average population. |
| CYP3A5 expressor (intermediate or extensive metabolizer) | Individuals who are CYP3A5 expressors have active enzyme activity and tend to metabolize and clear medications from their bodies more quickly than the average population. An increased starting dose of a medication is recommended for these individuals to achieve therapeutic effects. |
TPMT and NUDT15 are enzymes which help breakdown thiopurines (used in the treatment of acute lymphoblastic leukemia, autoimmune disorders like Crohn’s disease and rheumatoid arthritis, and organ transplants) such as azathioprine, 6-mercaptopurine and thioguanine into inactive metabolites. Genetic variations in the TPMT and NUDT15 genes change the metabolic activity of the enzymes, and as a result, the thiopurines are not broken down fast enough. This reduced metabolic activity can greatly increase the side effect profile and toxicity of thiopurines. Low to undetectable TPMT and NUDT15 enzyme activity is a risk factor for the development of azathioprine-induced, 6-mercaptopurine-induced or thioguanine-induced bone marrow suppression in individuals receiving ‘standard’ doses of the medication. Dose adjustments based upon TPMT and NUDT15 enzyme activity reduce the likelihood of developing thiopurine-induced side effects.
The PGx test at SickKids will predict both TPMT and NUDT15 enzyme activity. Enzyme activity can generally be grouped into three different categories: Poor metabolizer, intermediate metabolizer or normal metabolizer.
Metabolizer activity and effect on medication response of TPMT and NUDT15:
| Metabolizer Activity | Effect on Medication Response |
|---|---|
| Poor Metabolizer (PM) - lack of enzyme activity |
Poor to no enzyme activity leading to high risk of developing bone marrow suppression due to very reduced to no medication elimination and increased exposure to cytotoxic thioguanine nucleotides. Drastically reduced dosage of standard dosing is recommended in order to avoid severe side effects. |
| Intermediate Metabolizer (IM) - reduced enzyme activity | Reduced enzyme activity leading to reduced medication elimination and increased exposure to cytotoxic thioguanine nucleotides. Dose reduction of standard dosing is recommended in order to avoid side effects. |
| Normal Metabolizer (NM) - normal enzyme activity | Average enzyme activity and medication performance based upon medication label specifications. |
Warfarin is an anticoagulant (blood thinner) commonly used to prevent blood clots. It is prescribed for patients with a history of atrial fibrillation, recurrent stroke, deep vein thrombosis, pulmonary embolism, patients who have had heart valve replacements, and for the prevention of blood clots associated with autoimmune diseases and clotting disorders.
Warfarin dosing is monitored regularly by coagulation testing to maintain the international normalized ratio (INR) within specific limits in order to prevent risk of bleeding or clot formation. Warfarin is broken down in the liver by CYP2C9 to its inactive metabolites. Some variations in the CYP2C9 gene can lead to decreased activity of the CYP2C9 enzyme that may impact warfarin blood levels, increasing the risk of bleeding episodes.
Warfarin exhibits its anticoagulant (anti-blood clotting) effect by blocking the formation of vitamin K dependent-clotting factors. Vitamin K epoxide reductase enzymatically converts vitamin K into its active form, which is needed to produce clotting factors. Certain genetic variants in the VKORC1 gene may decrease the level of active vitamin K, thus causing fewer clotting factors to be available. This has an influence on warfarin dosing and sensitivity. A reduced warfarin dose may be required to elicit the same anticoagulant response.
PGx test at SickKids will check for known variants in the CYP2C9 and VKORC1 genes and may be incorporated with non-genetic factors to help predict correct warfarin dosing.
SCLO1B1 is a gene that encodes for a transport protein that is important for clearing medications from the body through the liver. Statins are a class of medications that help lower cholesterol levels and reduce the risk of heart attacks and strokes. Some genetic variants in the SLCO1B1 gene reduce the transport activity and may increase blood levels of statins. This increases the risk of developing statin-induced side effects, in particular muscle pain and muscle toxicity. Dose adjustments based upon SLCO1B1 function reduces the likelihood of developing statin-induced side effects.
The PGx test at SickKids will predict SLCO1B1 function. Function can generally be grouped into three different categories: Low function, intermediate function or normal function.
Transporter function and effect on medication response of SCLO1B1:
| Transporter function | Effect on Medication Response |
|---|---|
| Low function | Significantly reduced medication transport activity: lower statin dose should be given. If suboptimal efficacy is achieved an alternative statin may be considered (e.g. pravastatin or rosuvastatin). |
| Intermediate (medium) function | Reduced medication transport activity: lower statin dose should be given. If suboptimal efficacy is achieved an alternative statin may be considered (e.g. pravastatin or rosuvastatin). |
| Normal function | Normal medication transport activity: desired starting dose can be given, and doses of statin are adjusted, based on disease-specific guidelines. |
F5 is a gene that encodes for a clotting factor that helps blood clot. Some genetic variants in F5 may increases the risk of developing abnormal blood clots, or thrombosis, in particular of the legs and lungs. Hormone preparation that contains estrogen increase the risk even further to develop blood clots. Therefore, women who carry F5 variants should avoid taking estrogen-containing medications, such as oral birth control.
The PGx test at SickKids will determine the presence of F5. There are three possible results: Present, heterozygous or homozygous.
Cofactor presence and effect on medication response of Factor V Leiden:
| Cofactor Presence | Effect on Medication Response |
|---|---|
| Factor V Leiden Present | The patient has no increased risk from thrombosis. |
| Factor V Leiden heterozygous - only one copy of the gene with variant was inherited, either from mother or father |
If the patient has a family history of thrombosis or has had previous thrombosis: Avoid the use of hormone estrogen containing preparation. If the patient does not have a family history of thrombosis or has not had previous thrombosis: Advise the patient to avoid additional risk factors for thrombosis such as smoking. |
| Factor V Leiden homozygous - two copies of gene with variant were inherited, one from each parent |
If the patient has a family history of thrombosis or has had previous thrombosis: Avoid the use of hormone estrogen containing preparation. If the patient does not have a family history of thrombosis or has not had previous thrombosis: Advise the patient to avoid additional risk factors for thrombosis such as smoking. |
Who interprets and reports the pharmacogenetics test results?
Specialists from the Division of Clinical Pharmacology and Toxicology at SickKids will provide a detailed PGx report based on published clinical practice guidelines* as well as PGx data and information available in medication labels. The specialist will also provide a personal and clinically relevant consultation in a collaborative setting with the responsible health-care provider.
The health-care provider who requested the testing will obtain a copy of the testing results and recommendations. The detailed PGx report will also be stored in the patient’s electronic health record (Epic) at SickKids. In order to receive the report or have the report available in the patient’s electronic health record, participation in a pre- and post-consultation session is required, to understand the value and limitations of the PGx results for their medication therapy.
*Clinical practice guidelines are published by the following organizations: CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: Dutch Pharmacogenetics Working Group; CPNDS: Canadian Pharmacogenomics Network for Drug Safety; FDA: U.S. Food and Drug Administration
Who will have access to the pharmacogenetics test results?
The PGx test report will be stored in the Electronic Health Records System (Epic) at SickKids and a copy of the report will be sent to the patient’s referring physician and family doctor. The Personal Health Information Protection Act (PHIPA) ensures that personal health information cannot be given out to anyone without written permission. Therefore, only health-care providers involved in a patient’s care at SickKids have access to these test results and health records.
Tamorah Lewis
Division Head, Clinical Pharmacology and Toxicology
Ruud Verstegen
Staff Physician, Clinical Pharmacology and Toxicology
Iris Cohn
Director, Pharmacogenomics Program, Clinical Pharmacology and Toxicology
Sierra Scodellaro
Program Manager, Pharmacogenomics Program, Clinical Pharmacology and Toxicology
April Kennedy
Pharmacogenomics Data Analyst, Clinical Pharmacology and Toxicology
Have a question about the PGx research study?
PGx testing at SickKids is currently only available for eligible patients via clinic referral. The Clinical Pharmacogenetics Research Pilot Study operates out of the Drug Adverse Reaction and Toxicology (DART) Clinic. For information about PGx at SickKids, please contact the DART team.