How is pharmacogenomics being used beyond cancer?

• Pharmacogenomics is a relatively new field that combines the science of drugs (pharmacology) with the study of genes (genomics).
• Using pharmacogenomics, drugs can be targeted to conditions that are caused by specific genetics, genomics or underlying biology.
• Here, we look at how doctors are using pharmacogenomics to match people with HIV, arthritis and high risk of blood clotting to the best treatment for them.

Abacavir and HIV

Genetics has dramatically reduced the number of people suffering side-effects to HIV medicines. One example is abacavir, a drug used in conjunction with other antiretrovirals in the treatment of HIV infection.

Abacavir is a highly effective treatment for HIV (the virus that causes AIDS) – but around five to eight per cent of patients suffer severe side-effects, such as rash, fatigue and diarrhoea.

The nature of these symptoms suggested to scientists that these patients were suffering a ‘hypersensitivity’ reaction. This means that their immune systems were producing an exaggerated response to the drug, like an allergy.

This in turn suggested that the genes controlling their immune system’s responses – located in the major histocompatibility complex (MHC) – might be responsible for the side effects they were experiencing.

The scientists’ theory turned out to be correct. In 2002, two groups identified a particular gene variant in the MHC, called HLA-B*5701, as being the key factor in hypersensitivity to abacavir.

The HLA-B*5701 allele occurs at a frequency of around 5% in European populations, 1% in Asian populations and less than 1% in African populations. We now know that screening patients for HLA-B*5701 before treatment has dramatically reduced the number of side effects being experienced from abacavir use.

In individuals found to have the HLA-B*5701 allele, abacavir is avoided, and alternative HIV treatments are given. The test is highly cost effective and is now a routine part of clinical practice in the UK.

Azathioprine and rheumatoid arthritis

Azathioprine is a drug that dampens the activity of the immune system, helping organ transplant operations to be more effective and to treat a variety of inflammatory and autoimmune diseases, such as rheumatoid arthritis.

Azathioprine is an immunosuppressant, which means that it dampens the activity of the body’s immune system. It is used to help prevent rejection after organ transplant operations and also to treat a variety of inflammatory and autoimmune diseases such as rheumatoid arthritis.

In some people who take azathioprine, the drug is not activated in the body properly. As a result, unconverted azathioprine builds up in their bone marrow, killing their developing white blood cells and leaving them vulnerable to infection.

The conversion of azathioprine into its active form is catalysed by an enzyme called thiopurine S-methyltransferase (TPMT). Some variants of the gene encoding TPMT mean individuals cannot complete this conversion – this is when the unconverted azathioprine builds up in their bone marrow.

Before being given the drug azathioprine, people with rheumatoid arthritis can now be tested to find out which variant of the TPMT gene they have, and whether azathioprine will work for them.

Warfarin and people at risk of blood clots

Warfarin is an anti-coagulant, an agent that prevents blood clots forming. Pharmacogenomics is helping doctors to provide patients with the right dose of warfarin. It works by interfering with an enzyme involved in the blood clotting process, called vitamin K epoxide reductase.

Warfarin is most commonly prescribed to people who:

• have had a condition caused by a blood clot, such as deep vein thrombosis (DVT: blood clots in the legs) and pulmonary embolism (PE: blood clot in the lungs).
• are at risk of developing a blood clot, such as if they have artificial heart valves.

Although now widely used, doctors must be careful to provide the correct dose of warfarin to their patients. If the dose is too low it will have no effect, but if it’s too high the patient is at risk of uncontrolled bleeding.

Several factors affect the dose a patient needs, one of which is their genes. Many studies have focused on identifying the genetic factors influencing an individual’s response to warfarin. These studies have found that there are two types of genetic changes involved:

• those affecting the breakdown of warfarin by enzymes in the liver. These are called the cytochrome P450 genes.
• those involved in how the drug slows down blood clotting.

Because warfarin works by interfering with the enzyme vitamin K epoxide reductase, variations in the gene coding for this enzyme (VKORC1) can affect an individual’s sensitivity to warfarin. We also know that other factors, like age and weight, can play a role in the warfarin response – but not all factors have been identified.

Doctors currently rely on their clinical judgement to usually determine the correct dose of warfarin, starting at a very low dose and working up until the optimum dose is reached.

With further research it is hoped that it may become possible to develop a test to determine exactly what the correct dose should be, on a case-by-case basis using genetic information from the patient.