Pharmacogenetic Tests

Why is pharmacogenetics important?

When starting a patient on a drug to treat a particular condition, doctors typically prescribe one of several appropriate drugs. The dose and timing are usually based on the rate of metabolism and clearance from the body in the average person. They begin by prescribing a ​“standard” dose based on factors such as weight, sex, and age, and then adjust the dose or change the drug over time, depending on whether the patient’s condition is responding to the medication and whether the patient is experiencing unpleasant or dangerous side-effects. Sometimes, a patient may find that a treatment that has been working well for them suddenly does not work so well or causes side-effects when they start taking an additional drug.

The concentrations of some drugs are monitored with blood tests and the dosages increased or decreased to maintain the drug level in an established ​“therapeutic” range. Follow-up in this way is called ​“Therapeutic Drug Monitoring”. If changing the drug dose is not effective in treating or controlling the patient’s condition, or side-effects persist, then the patient may be given a different drug and the process is started again.

In contrast to this rather practical approach, pharmacogenetics is now beginning to offer doctors the opportunity to individualise drug therapy for patients based on their genetic make-up and get the dosage right from the start. Testing people before treatment is initiated in order to predict the way in which they are likely to respond to certain classes of drugs is an important emerging area of laboratory testing. This genetic information could help both the doctor and the patient when choosing current and future drugs and doses. For certain drugs, pharmacogenetic testing is already helping doctors predetermine drugs and doses that have the best chance of achieving the desired therapeutic effect while reducing the likelihood of side-effects.

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 their mother and one copy is inherited from their father. Each gene is made up of a specific genetic code, which is a sequence of basic units called nucleotides. Each nucleotide can be one of four different types (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 their genes, that person is said to have a heterozygous variant. If an individual has the same variant nucleotide in both copies of their 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 — they do not produce any known negative effect or may be associated with features like height, hair colour, and eye colour. 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 the immune response. Pharmacogenetic tests can determine if a variant is heterozygous or homozygous, which can affect an individual’s response or reaction to a drug.

When are the tests requested?

A doctor may test a patient’s genes for specific variations that are known to be involved in variable response to a drug at any time during treatment (for example, prior to treatment, during the 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 to the specific individual. Sometimes, the doctor may use this information to adjust the medication dose or sometimes to choose a different drug. Pharmacogenetic testing is intended to give the doctor 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 genes known as CYP2C9 and VKORC1.

Testing may be ordered prior to starting specific drug therapies or if someone who has started taking a drug is experiencing side-effects or having trouble establishing and/​or maintaining a stable dose. Sometimes patients 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

There are currently a variety of pharmacogenetic tests that can be requested on a clinical basis. Some tests may only be applicable to specific ethnic groups. The following are some drugs for which pharmacogenetic tests are available:

• Drug	Associated Diseases/​Conditions	Gene(s) Tested
  Warfarin	Excessive clotting	VKORC1 and CYP2C9
  Thiopurines (azathioprine, mercaptopurine, and thioguanine) (see TPMT)	Autoimmune/​Childhood leukaemia, inflammatory bowel disease	TPMT

Is there anything else I should know?

For most drugs, pharmacogenetic tests are generally not widely requested for a variety of reasons. However, they may be indicated when the medication of interest has a narrow therapeutic range and/​or is associated with a high rate of adverse events. Pharmacogenetic testing is in its early stages in the UK, with the exception of TPMT testing which has an established role in treatment of leukaemia and inflammatory bowel disease. The UK 100,000 Genomes Project, which was established to look for previously unknown genetic variation in people with cancer or rare conditions, may provide us with information on other areas where pharmacogenetics could be used to tailor therapy to the patient.

• Pharmacogenetic tests are intended to provide the doctor and patient with additional information when selecting drug treatments and dosages. For a better understanding, patients may want to consult with a genetic counsellor prior to and after having a pharmacogenetic test performed. Genetic counselling and informed consent are recommended for all genetic testing.

  To learn more about the role of pharmacogenetics in personalized medicine, visit the Royal Society’s Personalized Medicine website.