Genetics and its role in personalised medicine

Owing to advances in genomic technology, the days of personalised medicine are truly upon us. Personalised medicine, also called precision or individualised medicine, is an evolving field of practice in which physicians use genomic information to guide the optimal course of treatment. Personalised medicine recognises the individuality of every patient who walks into a medical practice, and acknowledges that each patient will require their own unique intervention to ensure optimal health outcomes. Keywords: genetics, personalised medicine

Introduction

One of the most significant technological accomplishments in recent history was the complete sequencing of the human genome. This was a collaborative effort spanning fifteen years and involving scientists and academics from around the globe. When the first draft was published in 2003, almost two years ahead of schedule, it gave us the ability, for the first time, to read nature’s complete genetic blueprint for building a human being. It also created an expectation that with detailed knowledge of the genome would come insights into the prevention and management of disease. However, sequencing the human genome heralded only the first (major) step in this direction. The research potential that was unlocked, to identify the disease causing genes and the changes in gene expression that may initiate a disease process, has brought us much closer to the eventual implementation of precision medicine.

The Human Genome Project has helped to create a healthcare environment that is not only personalised but also predictive. One of the key drivers of the burgeoning “wellness” environment is the desire of individuals to take more responsibility for their own health. One aspect of this entails taking proactive steps to prevent disease, rather than relying on the healthcare system to cure the disease only after it manifests. Given that the massive burden of chronic disease with which we are faced is predominantly lifestyle driven, there is much that the average health-conscious individual can do to reduce this burden.

The Human Genome Project has helped to create a healthcare environment that is not only personalised but also predictive. One of the key drivers of the burgeoning “wellness” environment is the desire of individuals to take more responsibility for their own health. One aspect of this entails taking proactive steps to prevent disease, rather than relying on the healthcare system to cure the disease only after it manifests. Given that the massive burden of chronic disease with which we are faced is predominantly lifestyle driven, there is much that the average health-conscious individual can do to reduce this burden.

At the intersection of genetic testing and personalised medicine lies the understanding that recommendations given to one person on diet, nutrition and lifestyle, are not necessarily the same recommendations given to another person. We know this intuitively, as our propensity to hop from one weight loss program to another testifies. With the benefit of foresight provided by a DNA test, those days are behind us. Individuals can be informed of the most suitable diet type for weight management, the specific nutrients their bodies require for optimal cellular health, the most suitable exercise regime according to their genetic potential, and they can be empowered by this knowledge to make the most appropriate and relevant lifestyle and medical choices.

Nowhere has the advent of personalised medicine been more apparent than with the advances in the field of pharmacogenomics – a field of study that explores the relationship between genetic variations and differences in drug metabolism. The adoption of pharmacogenomics (PGx) in clinical practice promises more effective decision-making regarding drug selection and dosing,1 and offers several ways in which to individualise drug treatment, including drug selection, drug dosages, maximising effectiveness and minimising undesirable side effects.

The successful implementation of effective genetic testing as part of clinical prescribing could prove highly beneficial to the physician, the patient and the funders. The risks of adverse drug reactions (ADR) are very real. Of the 27 drugs frequently cited in ADR studies, 59% are metabolised by at least one enzyme that has a variant allele known to cause poor metabolism.3 A recent meta-analysis in the United States of America suggested that ADRs are the fourth most common cause of death.4 Reducing ADRs clearly has significant benefits for patient safety as well as to reduce the costs of further treatment or recovery.

Pharmacogenomics also provides benefits compared to current approaches to therapeutic drug monitoring. In contrast to traditional monitoring, “testing can be undertaken before treatment begins, does not require the assumption of steady state conditions (or patient compliance) for the interpretation of results, could be performed less invasively (e.g. with mouth swabs) and could provide predictive value for multiple drug substrates rather than a single drug, and would be consistent over an individual’s lifetime”

Pharmacogenomics in practice

Pharmacogenomics testing reduces the need to use the trial-and-error method for managing medications that could have significant side effects or might not even be effective in certain types of patients. For example, codeine, oxycodone, hydrocodone and similar drugs all carry a warning about prescribing them to patients who are ultra-rapid metabolisers by virtue of their CYP2D6 enzyme function. This is because these drugs are pro-drugs that are converted to morphine as the active metabolite, and ultra-rapid metabolisers will convert these drugs to morphine at a much faster rate. This results in higher levels of circulating morphine leading to serious adverse effects. Avoiding these opioids in ultra-rapid metabolisers prevents potentially adverse or deadly events.

Another example is the commonly prescribed drug Plavix, prescribed to patients who have had a cardiovascular event with the aim of preventing a secondary event. Prescribing Plavix to a patient who does not metabolise the pro-drug into its active form reduces the anticoagulant efficacy of the drug. An alternative therapy should be prescribed for these patients.

Another example is the commonly prescribed drug Plavix, prescribed to patients who have had a cardiovascular event with the aim of preventing a secondary event. Prescribing Plavix to a patient who does not metabolise the pro-drug into its active form reduces the anticoagulant efficacy of the drug. An alternative therapy should be prescribed for these patients.

If a physician can accurately select the correct medication at the correct dose during the first patient visit, the healthcare system will benefit in the following ways, impacting healthcare cost:

  • Reduced number of clinic visits to either titrate medications or
    select new medications
  • Reduced total medication cost as fewer pills are “wasted”
    because the medication is not effective.
  • Improved efficiency and time saved in managing patients.
  • Reduced risk of ADR-related hospitalisation
  • Increased medication adherence.

There is a growing number of examples of pharmacogenomics tests used in clinical practice6-8 and the potential of pharmacogenetics to enhance patient-specific pharmacotherapy is being increasingly recognised.9-11 The Pharmacogenomics Knowledge Base (PharmGKB) at Stanford represents an everexpanding resource for both researchers and clinicians to aid in their understanding of how variation in a person’s genetic makeup affects drug response. A key component of the PharmGKB is the Clinical Pharmacogenetics Implementation Consortium (CPIC) that provides freely available, peer-reviewed drug-dosing guidelines for clinicians in order to help them understand how available genetic test results should be used to optimise drug therapy. They provide resources for a wide range of frequently prescribed drugs, including medications relevant to cardiovascular disease, oncology, pain management and antipsychotics.

Cost-benefit analysis

When we look at the commercial value of pharmacogenomic testing, we should start with “high risk” patients first and preferably those patients who take more than one drug from the following drug classes, that account for 71%2 of all preventable ADR hospitalisations:

  • Antiplatelet drugs
  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
  • Diuretics
  • Anticoagulants
  • Beta blockers
  • Angiotensin converting enzyme (ACE) inhibitors
  • Angiotensin receptor blockers,
  • Cardiac glycosides
  • Opioid analgesics
  • Antidiabetic agents

A meta-analysis designed to assess the cost-effectiveness of pharmacogenomics testing over the course of a patient’s lifetime, found that for every 1 000 random 40-year-old individuals tested, 101 ADR-related emergency room visits and hospitalisations, and three deaths can be prevented.12 Thus, only looking at admissions (deaths excluded), for every 10 patients tested, at least one hospital admission can be prevented.

Out of hospital

In another study on the resource use of outpatients with anxiety and depression,13 it was found that patients on a medication regimen who are labelled as “problematic” according to the gene-based interpretive report had (i) 69% more total health care visits, (ii) 67% more general medical visits, (iii) greater than three-fold more medical absence days, and (iv) greater than four-fold more disability claims than subjects taking drugs who are categorised by the report as in either the green bin (“use as directed”) or the yellow bin (“use with caution”).

Conclusion

Since the completion of the Human Genome Project in 2003 and the prediction that by 2020 “the pharmacogenomic approach for predicting drug responsiveness will be standard practice for quite a number of disorders and drugs”,7 the research and clinical application of PGx has grown rapidly. PGx testing is now widely used around the world and presents an opportunity to enhance precision medicine techniques in many healthcare markets. The PharmGKB and CPIC guidelines allow practitioners to confidently use genetic testing to tailor prescribing programs to include a wide range of commonly used drugs for areas such as cardiovascular disease, pain management and anti-psychotics. In future, other pathologies will also be included and the breadth of PGx testing will expand.

In the era of personalised medicine, as we strive to provide tailored care and treatment to each individual, pharmacogenomic testing sits at the pinnacle of evidence-based clinical applications. A significant number of drugs have labels with dosage guidelines based on genotype, and the availability of low-cost high throughput genotyping data means that these guidelines can finally be implemented in a clinical setting. It also means that more and more patients will be presenting the results of these tests, obtained themselves, to clinicians and expecting them to manage their prescriptions according to these reports.

Therefore, a key component in the incorporation of PGx data into the clinical decision-making process will be the education of clinicians. It needs to be emphasised that the test does not negate the standard precautions clinicians would have taken when prescribing medication. Lifestyle, nutrition, age and weight of the patient, and any concurrent medications the patient may be taking are all still important variables. Genetics is just another risk factor that can and should be considered.

References

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