How is pharmacogenomics being used?

HIV

Genetic testing 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.

In 2002, two groups identified a particular gene variant, called HLA-B*5701, as being the key factor in hypersensitivity to abacavir.

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 major histocompatibility complex (MHC), called HLA-B*5701, as being the key factor in hypersensitivity to abacavir.

Individuals with the HLA-B*5701 allele were found to be more likely to have a hypersensitivity reaction to abacavir.

The HLA-B*5701 allele occurs at a frequency of around five per cent in European populations, one per cent in Asian populations and less than one per cent in African populations.

The HLA-B*5701 allele occurs at a frequency of around five per cent in European populations, one per cent in Asian populations and less than one per cent in African populations.

Clinical trials have now shown 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.

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.

People with rheumatoid arthritis can have a genetic test to see if azathioprine will be an effective treatment for them.

In some individuals azathioprine is not activated in the body properly. As a consequence unconverted azathioprine builds up in their bone marrow, killing developing white blood cells and leaving the individual 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 do this conversion, and 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 possess and whether azathioprine will be an effective treatment for them.

Warfarin

Pharmacogenomics is helping doctors to provide patients with the right dose of warfarin.

Warfarin is an anti-coagulant, an agent that prevents blood clots forming.

Warfarin is an anti-coagulant, an agent that prevents blood clots forming. It works by interfering with vitamin K epoxide reductase, an enzyme involved in the blood clotting process. It 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), or
• who are at risk of developing a blood clot, such as people with artificial heart valves.

Although now widely used, doctors have to be careful with providing 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 bleeding.

Several factors affect the dose a patient needs, one of which is their genetic makeup. 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.

Despite knowing this, it is still difficult to apply this information in a clinical setting because not all of the factors affecting responses to warfarin have been identified. For example, age and weight also play a role.

At the moment, doctors rely on their clinical judgement and usually determine the correct dose of warfarin by 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.