What is pharmacogenomics?
Pharmacogenomics (PGx), often used interchangeably with the term pharmacogenetics, though a distinction can be made, is the science that examines the link between our genetic makeup and how we respond to medications. It encompasses the full spectrum, from laboratory studies to clinical trials and the development of practice guidelines.
Pharmacogenomics improves prescribing for the individual by helping to predict how they will respond to a particular medication and dose. Ultimately, improved decision-making when prescribing enhances therapeutic response, safety and health outcomes. In this way, pharmacogenomics forms an important part of the emerging paradigm of ‘personalised medicine’.
How do genetics affect drug response?
Understanding the basics of drug response requires an understanding of drug exposure (i.e. how the amount of drug at the site of action changes over time), and drug actions (i.e. how a drug produces effects through receptors, enzymes, ion channels and other targets). There are many factors that influence drug exposure and drug actions, of which an individual’s genetics form a significant part. Drug exposure can be changed by variations in the genes encoding the metabolising enzyme (e.g. CYP450 enzymes), producing either faster or slower rates of metabolism. These changes in enzyme function may change oral bioavailability or half-life which directly determine drug exposure and ultimately, the clinical effects. Most pharmacogenomic tests are for enzymes or transporters that influence drug exposure. Even though drug targets are key to drug response, we currently only test for the VKORC1 and OPRM1 genes, which predict warfarin and morphine sensitivity, respectively. The number of drug target genes is predicted to increase in the near future.
What are the myDNA Medication tests?
The myDNA multiple category test is a pathology test that identifies common variations in the genes encoding the enzymes CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP1A2 and CYP3A4. In addition, the following genes are also analysed: the VKORC1 gene predicting warfarin sensitivity, the SLCO1B1 gene predicting myopathy risk with simvastatin and the OPRM1 gene predicting morphine sensitivity. This test covers a range of medications from different therapeutic groups (including a range of analgesics, psychotropics, cardiovascular and gastrointestinal medications).
The myDNA single category test analyses the genes relevant for the type of report selected (ie Mental health, Pain, Cardiovascular or Gastrointestinal) and will cover certain drugs in that medication category. The myDNA medication Quick Reference List provides the main medications covered by each type of test.
The myDNA Medication test results are not intended to provide information on disease states or the risk of allergic reactions.
The myDNA medication reports provide the requesting practitioner with interpretation of genetic results and actionable recommendations, which may include suggestions for additional clinical monitoring or adjustment of drug or dose based on international pharmacogenomic guidelines.
The myDNA medication tests may therefore help to:
- Pre-emptively predict a patient’s response to certain medications;
- Facilitate personalised prescribing;
- Improve the chance of therapeutic success; and
- Reduce the risk of adverse effects.
How does genetic variability affect drug metabolism?
The liver is the major site of drug metabolism and here the body converts many medications into new compounds via enzyme-mediated chemical reactions. The enzymes that catalyse these reactions are encoded by genes. Many of these genes are polymorphic – that is, different variations exist in the population – and these variations directly influence how efficiently an enzyme will function. For example, some variations result in the production of a non-functional enzyme whereas others result in metabolic speeds that far exceed the ‘normal’ rate.
By testing an individual for common variations, it is possible to predict their corresponding enzyme activity and the speed at which relevant drug metabolism will occur.
Most drugs are administered in an active form and many of these are converted to inactive metabolites in the liver that are subsequently removed from the body (often via the kidneys or biliary tract). ‘Poor metabolisers’ inactivate these medications at a much slower rate than normal, and thus the active drug may accumulate in the body, reaching high plasma concentrations that potentially lead to significant side effects. Conversely, ‘ultrarapid metabolisers’ may not achieve adequate concentrations of active drug for therapeutic effect at standard doses. Changes in transporter function can also affect plasma concentrations and drug exposure. For example, if the function of the transporter SLCO1B1 (which facilitates the uptake of statins into the liver) is low due to a genetic change, there will be increased plasma concentrations and a higher risk of statin-induced muscle injury (especially with simvastatin).
By contrast, other drugs are administered in inactive forms (called pro-drugs) and bio-activated by liver enzymes. Poor metabolisers produce insufficient quantities of the active compound and are therefore unlikely to achieve a therapeutic effect.
Is pharmacogenomics evidenced-based?
Pharmacogenomics has been the subject of a large amount of research over the past two decades and a robust evidence-base now exists to support testing in a number of clinical scenarios. The Pharmacogenomics Journal1 is one example of a peer-reviewed journal dedicated to research in the field. The clinical utility of pharmacogenomics was recently summarised in a Nature publication titled ‘Pharmacogenomics in the Clinic’, which concluded that ‘there are now approximately 20 genes that affect about 80 medications that are actionable in the clinic’.
The Pharmacogenomics Knowledgebase (PharmGKB)2 is funded by the National Institutes of Health (NIH) in the United States and is managed at Stanford University. PharmGKB records pharmacogenomic-based dosing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC), which are published in the journal Clinical Pharmacology and Therapeutics when sufficient evidence allows such recommendations.
Currently, there are CPIC guidelines available for the dosing of 34 different medications which can be accessed at www.pharmgkb.org. The US Food and Drug Administration (FDA) has also published a list of over 150 drug labels that provides prescribing information based on pharmacogenomic biomarkers.
Several other international bodies have published guidelines for drug dosing based on pharmacogenomic testing, including the Royal Dutch Pharmacist’s Association Pharmacogenetics Working Group and the Canadian Pharmacogenomics Network for Drug Safety.
Are the test results relevant for the prescription of all medications?
The myDNA medication tests can provide useful information for the prescription of many medications used in clinical practice. Not all medications are covered by this test as some may not currently have a reliable genetic test that can inform prescribing considerations. See the myDNA medication Quick Reference List for a list of the main medications covered by these tests.
Which patients could benefit from pharmacogenomic testing?
Testing could be beneficial to patients commencing a medication covered by the test.
Testing may also be particularly useful for addressing specific clinical problems, including:
- A history of ‘sensitivity’ to medications;
- Experiencing significant side-effects;
- Poor therapeutic response to medications;
- Taking multiple medications; or
- Potential suitability for using doses outside the usual range.
Pre-emptive testing for all patients would allow the results to be available at the time of prescribing and can be incorporated immediately into decisions such as medication selection and dosing.
In some ways, pharmacogenomic test results could sit alongside the patient’s renal and liver function, as useful and highly relevant information for prescribing.
What is the relationship between an allele, genotype and phenotype?
An allele is a variant form of a gene. For each gene, an individual inherits an allele from both their mother and father and this combination is called their genotype. A phenotype is an observable characteristic that occurs as the result of the interaction between a patient’s genotype and their environment. In the case of drug-metabolising enzymes, an individual’s phenotype is the speed at which they actually process medications.
The basis of pharmacogenomic testing is the prediction of an individual’s phenotype from their genotype, which can be achieved with a good degree of reliability. An additional factor which may alter the genotype-predicted phenotype is the administration of medications that are enzyme inhibitors or inducers. For example, administration of a strong inhibitor of an enzyme may change the enzyme’s genotype-predicted phenotype from a Normal Metaboliser to a Poor Metaboliser. Therefore, any inhibitors or inducers identified in the patient’s current list of medications provided, will be flagged for the doctor in our myDNA medication reports. How strongly any pharmacogenomic result is linked to therapeutic or adverse effects with a specific drug, depends on many factors, for example, whether there are alternative pathways through which the drug in question may be metabolised. That link may be stronger or weaker depending on the specific gene-drug interaction. When a substantial evidence base points to a strong link between a gene and drug response, there is likely to be clinical utility in performing the pharmacogenetic test.
Which polymorphisms are included in the myDNA medication tests?
The myDNA medication tests identify the polymorphisms that correspond with the following alleles:
The ‘wild-type’ allele *1 is assigned when none of the tested variants are identified.
How common are the relevant polymorphisms?
Significant variability exists between ethnic groups with respect to the frequency of the genotypes tested. This is important in understanding the chance of a test missing an important genotype in a particular ethnic population. An analysis of a sample of 5,408 Australian patients tested by My DNA Life revealed the following frequencies4 (see table at bottom of page).
A comprehensive literature review conducted by Llerena et al. in 2014 summarised the reported frequency of CYP2D6 genotypes and phenotypes across different ethnic groups and geographic regions.3 For example, genotypes predictive of CYP2D6 poor metabolism were reported with a frequency of 8.7% in Scandinavians and genotypes predictive of CYP2D6 ultrarapid metabolism were reported with a frequency of 28.7% in Ethiopians.
How is this test different to a liver function test (LFT)?
Liver function tests measure a number of parameters that can provide an indication of liver inflammation/damage (ALT, AST), biliary system pathology (bilirubin, ALP) and synthetic capacity (albumin). Alone they are poorly predictive of hepatic drug metabolism, although combined with other clinical and blood markers of synthetic function (Child-Pugh classification) offer guidance in more significant liver disease.
However, LFTs provide very limited information on the ‘function’ of individual enzymes, which may be significantly abnormal in the absence of liver disease. For example, ‘poor metabolisers’ are genetically limited to producing non-functional enzymes and this is independent of any other liver pathology.
How accurate is the DNA test and reports?
A strict quality assurance process combined with state of the art laboratory facilities, allows us to control reliability and validity of our tests. Our reports and findings are developed in accordance to internationally recognised guidelines and factor in large number of published studies.
Is the test covered by Medicare or private health insurance?
Currently there is no reimbursement for the cost of these tests by Medicare or private health insurance in Australia. Testing, however, may be covered by WorkCover and DVA in certain circumstances.
How do I order a test and what is the cost?
A blood test can be ordered through Australian Clinical Labs or Genomic Diagnostics Pathology for analysis through a NATA accredited laboratory. The sample required is 4mls in an EDTA tube. This costs up to $197 for the myDNA multiple category test (myDNA PGx Multi). Other pathology providers may add an additional charge for blood collection. Through Genomic Diagnostics, a myDNA single category report for PGx Pain or PGx Mental Health can be ordered for $147.
Alternatively, the patient can be referred to a pharmacy participating in the myDNA program for a cheek swab, at a cost of $149 for the myDNA multiple category test and $99 for any of the four single category tests (see https://www.mydna.life/pharmacy-finder/ for locations).
It is also possible for a patient to purchase a cheek swab kit through the myDNA website and have the results sent directly to their treating doctor. The cheek swab and blood sample results are the same. Results are typically available 10-15 business days after the laboratory has received the sample. Reports are sent via fax or through a secure myDNA online partners portal.
The patient can be tested and remain on their current medications as the myDNA test is a genetic test and medications will not affect the genetic results.
Should testing be repeated when a new drug is prescribed?
A gene test result doesn’t change over the course of a person’s life. Therefore, testing for a specific genetic variant can be conducted once and used to guide both current and future medication prescriptions. As new genetic tests are developed that may be important for understanding the processing of or response to medications, it is possible that further testing may be warranted in the future.
1. See http://www.nature.com/tpj/
2. See https://www.pharmgkb.org/
3. Llerena, A., et al. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert opinion on drug metabolism and toxicology. 2014 Nov; 10(11): 1569-1583
4. Mostafa S, Kirkpatrick CMJ, Byron K, Sheffield L. An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. J Neural Transm (Vienna) 2018.