What is pharmacogenomics?

A type of personalised medicine

• People respond differently to medicines. Most respond well and their health improves. Some do not gain any benefits from the treatment, and a minority suffer from side effects.
• After you take a drug, it gets processed (metabolised) by your body.
• How the drug is processed and how you respond to it is determined, in part, by your genes.
• These genes affect the machinery that is responsible for processing the drug.
• Understanding how different genetics affect how a drug is processed can help doctors to more accurately determine which drug and which dose is best for individual patients.
• Pharmacogenomics is when scientists look at the genome of an individual to identify the genetic factors that influence their response to a drug.
• By finding these genes, medical researchers hope to develop genetic tests that will predict how patients are going to respond to a drug and the dose they should be given.
• In the future, doctors may be able to identify which drugs are best for their patients through the results of these tests.
• This will help them identify the drug that will best treat their disease and is least likely to cause side effects. This is personalised medicine.
• As well as reducing the risk of side effects, another huge advantage of using pharmacogenomics is that it allows for more efficient use of treatments.
• For example, some cancer treatment can be very expensive but may only be effective in a small subset of patients.
• With a better understanding of the disease and the treatment through pharmacogenomics, resources can be focused on treatments that are more likely to be effective in a patient, irrespective of cost.

We are all different

• The reason people vary in their responses to drug treatments lies in the genetic differences, or variation, between them.
• Following the Human Genome Project, research has focused on comparing human genomes to understand genetic variation and work out which genetic variants are important in health and the way we respond to drugs.
• Two types of variation are common in the human genome:
  • Single nucleotide polymorphisms (SNPs): changes in single nucleotide bases (A, C, G and T).
  • Structural variation: changes affecting chunks of DNA which can consequently alter the structure of the entire chromosome. Structural variation can happen in a number of ways, for example:
    • Copy number variation (CNV): when there is an increase or descrease in the amount of DNA. This can be due to:
      • deletion: where an entire block of DNA is missing
      • insertion: where a block of DNA is added in
      • duplication: where there are additional copies of a section of DNA.
    • Inversion: when a chromosome breaks in two places and the resulting piece of DNA is reversed and reinserted back into the chromosome (the opposite way round).
    • Translocation: when genetic material is exchanged between two different chromosomes.
• SNPs are like changing a single letter in the metaphorical ‘recipe book of life’, while structural variation is the equivalent of whole paragraphs or pages being lost or repeated.
• Scientists have been aware of SNPs for a long time, but the extent of structural variation, in particular copy number variations, has only been revealed since it’s been possible to sequence and compare many genomes.
• Structural variation appears to be quite common, affecting around 12 per cent of the genome. It has been found to cause a variety of genetic conditions.

Finding disease variants

• Humans share around 99.5 per cent of their genomes.
• The 0.5 per cent that does differ between each of us affects our susceptibility to disease and response to drugs.
• Although this doesn’t sound a lot, it still means that there are millions of differences between the DNA of two individuals.
• For example, SNPs are common in the genome. It is therefore difficult to work out which single letter changes cause disease and which are passengers that have just come along for the ride and have no effect on health.
• So how is it possible to know which genetic variants cause disease and which are passengers?
• The way scientists look at disease variants is to compare the genetic makeup of a large number of people who have a specific disease with those that do not.
• This allows scientists to look for genetic variants that are more common in people with a disease compared to people without the disease.
• For example, if a particular genetic variant is present in 80 per cent of patients with the disease but only 20 per cent of the healthy population it could be a sign that that variant is increasing the risk of that disease.
• However, looking for a disease that is caused by variants in a single gene is the simplest example.
• There are many complex diseases where variants in many different genes might be involved.
• So, for this type of comparison to be effective very large groups of people need to be studied, usually in the tens of thousands, to find the variants with subtle effects on disease risk
• Researchers also try to pick individuals with similar phenotypes, in both the disease and healthy groups, so that the disease genes are easier to identify and study.

Challenges of pharmacogenomics

Although pharmacogenomics is likely to be an important part of future medical care, there are many obstacles to overcome before it becomes routine:

• It is relatively rare for a particular drug response to be affected by a single genetic variant.
• A particular genetic variant may increase the likelihood of an adverse reaction but it will not guarantee it.
• As a result some people with the variant may not experience an adverse reaction to a drug.
• Similarly, if an individual doesn’t have the gene variant it doesn’t guarantee they won’t experience an adverse reaction.
• There are often a large number of interacting genetic and environmental factors that may influence the response to a drug.
• Even when associations between a genetic variant and a drug response have been clearly demonstrated, suitable tests still have to be developed and proved to be effective in clinical trials.
• A test that has succeeded in a clinical trial still has to be shown to be useful and cost-effective in a healthcare setting.
• Regulatory agencies will have to consider how they assess and license pharmacogenetic products.
• Health services will have to adjust to new ways of deciding the best drug to give to an individual.
• The behaviour of individual doctors will need to change.
• A lot of side effects are due to patients not taking their drugs as prescribed or doctors prescribing the wrong dose.

Some examples of pharmacogenomics working effectively, for example abacavir and HIV, show that these challenges can sometimes be overcome. However, in most cases, introducing the findings from pharmacogenomics is likely to be a complicated process.