What is pharmacogenetics?

Medicines are the most common therapeutic intervention in healthcare, yet the efficacy and safety of many drugs show considerable inter-personal variation. Some patients are prescribed inefficacious medication, whereas others develop adverse drug reactions.

This variation has a significant personal, clinical, and economic impact, leading to poorer individual and societal outcomes. Strategies are required to reduce this variability. One approach is to leverage the knowledge of an individual’s genetic information to support medicines optimisation, better informing medicine selection, and dosing. This is a concept known as pharmacogenetics.


What is the difference between pharmacogenetics and pharmacogenomics?

Pharmacogenetics is the study of genetic causes of individual variations in drug response, whereas pharmacogenomics is the study of how a patient’s genome can influence how they respond to medicines. Variants in an individual’s genome can increase the function of medicines or make them less effective.

Consider three patients in pain, all prescribed the same dose of codeine. The first patient responds appropriately, and the second patient appears to receive no analgesic relief, whilst the third patient develops symptoms of opioid toxicity. Such variation in response and side effects are a frequent and often frustrating feature of clinical practice.

Such variation is regularly attributed to the chosen dosing strategy, the accuracy of the initial diagnosis, or individual factors, such as co-morbidities, polypharmacy, or compliance. However, genetics also plays a role. Codeine requires activation to morphine by the liver enzyme called CYP2D6. Common genetic variants impact the function of the CYP2D6 enzyme. Considering the above scenario, the second patient, like 10% of the population, may be a poor CYP2D6 metaboliser, meaning that they fail to effectively convert codeine into morphine. Meanwhile, the third patient may represent approximately 2% of individuals who are ultra-rapid CYP2D6 metabolisers, in danger of producing high morphine levels, leading to toxicity.


How is it useful to my practice?

Evidence-based guidelines to support pharmacogenetic-guided prescribing are available for many commonly prescribed medicines. Despite a good understanding of these medicine-gene relationships, clinical implementation in the UK is limited to a small number of medicines. This is typically carried out reactively, where single genes are analysed when a medication is considered.

Given the high population frequency of genetic variation which influences the efficacy and safety of medicines, an alternative approach to pharmacogenetic guided prescribing is pre-emptive panel testing. This involves testing individuals for many common pharmacogenetic variants at a set time, irrespective of the medicine they are prescribed. This information can then be integrated into a patient’s medical records and used to inform prescription.

A 2018 analysis of primary care prescribing found that PPIs, statins, antiplatelets, and antidepressants were some of the most prescribed items. All of these classes of medicine have guidelines for genotype-guided prescribing. As such, panel testing could be a powerful approach to optimise an individual’s whole prescription, rather than a single medicine. In addition, once generated, these data will remain valuable throughout an individual’s life.


How can pharmacogenetics be delivered in general practice?

Academics and clinicians in Manchester have recently received funding to develop a pilot pharmacogenetic service. This is known as the PROGRESS programme. The work will attempt to integrate pharmacogenetic data into electronic health records in primary care. The study will monitor how physicians in general practice can use this data.

When pharmacogenetic results are required very quickly, an alternative approach is rapid point of care genotyping. The Pharmacogenetics to Avoid Loss of Hearing (PALOH) study shows that this approach is possible. The results were published last month in JAMA Pediatrics and a video is also available on our home page.



Acknowledgement: Dr John McDermott, NIHR Doctoral Research Fellow in Genomic Medicine, and Professor Bill Newman, NHS North West Genomic Medicine Service Alliance Clinical Director.