Pharmacogenetics: How our genes influence our drug response

Have you ever wondered why a particular cold medicine works wonders for your partner but always gives you a headache? This type of variability from person to person is true for nearly every medication from your over-the-counter cold and flu medicine to antibiotics and cancer treatments.

This phenomenon is known as pharmacogenetics, and describes how our genetics affects our response to medications. This variability can have wide-ranging implications for dosing, therapeutic sensitivity, drug efficacy, likelihood of side-effects, and the risk of adverse drug reactions (ADRs).

The advent of next-generation sequencing (NGS) now means that we can analyse whole genomes and start building up a comprehensive database of well-characterized drug-gene interactions. In the future, this could be used in personalized medicine to guide treatment recommendations, potentially avoiding severe side effects, ineffective treatment, and ensuring appropriate dosages.

In recent years, NGS approaches have been extensively applied at a large scale to identify and characterize potentially functional variation in human genes that relate to drug response. This blog will explore the importance of pharmacogenetics and its increasing role in personalized medicine.

The basics of pharmacogenetics

The world of medicine often operates on a “one size fits all” approach when it comes to drugs. However, what many fail to recognize is that these medications don’t yield uniform results for everyone. Predicting who will benefit, who won’t respond, and who might experience ADRs remains a challenging puzzle.

Genetic diversity among individuals significantly impacts how drugs interact within our bodies, mainly through pharmacokinetics and pharmacodynamics. Pharmacokinetics describes how drugs are processed by the body—how they’re absorbed, distributed, metabolized, and excreted. For example, the CYP2D6 gene influences the pace at which many crucial medications, from antidepressants to opioids, are metabolized [1]. Variations in this gene can determine how rapidly an individual metabolizes a drug. Those with either inefficient or exceptionally rapid metabolism face a higher risk for ADRs or treatment failure when prescribed drugs are metabolized or bioactivated by CYP2D6.

On the other hand, pharmacodynamics is concerned with the effect that drugs may have on the body in terms of both treatment and side effects. Specific genetic variations can significantly elevate the likelihood of severe ADRs. For example, a gene variant known as HLA-B*15:02 is associated with the increased likelihood of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), when treated with carbamazepine, a highly effective epilepsy drug [2].

In 2015, a systematic review found that 3.6% of patients in Europe were hospitalized due to ADRs and 10% of patients developed side effects during their in-patient stay [3]. Given the large number of genes involved in drug metabolism and transport, it’s crucial that we can identify potential genetic variations that could contribute to critical ADRs and ineffective treatments.

The beginning of personalized prescribing

Every day, millions of people are taking medications that will not help them. Take, for instance, the top ten highest-grossing medications in the United States; research reveals that they’re effective for only a fraction of those who take them, ranging from 1 in 25 to 1 in 4 [4]. In fact, for some drugs like statins, commonly used to lower cholesterol, as few as 1 in 60 people might experience any benefits [5].

Because of this, there is an increasing recognition that researchers and clinicians need to take individual genetic variability into account when conducting clinical trials for new and existing drugs, and when prescribing drugs. Numerous trials are now underway to explore the implementation of patient genotyping before prescription [6-8]. These trials include using genotyping for individual-based dosing of warfarin [6], tailored dosing of thiopurines in children with acute lymphoblastic leukemia [7], and to prevent the loss of hearing in neonates [8].

The Pharmacogenetics to Avoid Loss Of Hearing (PALOH) study assessed the implementation of a point-of-care (POC) genetic test that could prevent hearing loss in neonates [8]. Annually, approximately 90,000 babies in the UK are admitted or assessed in neonatal intensive care units, where infections pose substantial risks. The National Institute for Health and Care Excellence (NICE) recommends immediate treatment for suspected or confirmed early onset neonatal infection using a combination of gentamicin and benzylpenicillin. It’s particularly important that this treatment is given within an hour of diagnosis as this ‘golden hour’ significantly influences clinical outcomes [9].

However, one in 500 babies have a genetic change called m.1555A>G which predisposes them to irreversible, profound hearing loss after a single dose of gentamicin. A POC genetic test that can rapidly identify neonates with this genetic mutation could potentially save approximately 200 babies annually from irreversible deafness in the UK. Following a trial conducted in the Manchester University NHS Foundation Trust (MFT), NICE has now recommended this world-first genetic test for use within the NHS [10].

Figure 1. The benefits of using genetics to guide treatment

While initiatives like this are hugely important for tailoring treatments and preventing any serious side effects, they tend to only target a small subset of genetic mutations and conditions. Genome wide association studies (GWAS) are continually discovering more associations between genetic variants and both drug efficacy and ADRs [11]. For personalized medicine to become more accessible, widespread, and effective, it’s crucial that genotyping tests in the future can identify a wide range of genetic variants and their potential implications for drug treatments.

The future of prescription

Most pharmacogenetic tests are done in a reactive manner, usually in the context of prescribing a specific medication or class of medications. However, this process can be expensive and slow, and means delaying treatment for a patient every time that they need a new prescription [12].

However, pre-emptive screening of a large number of genes before any prescriptions are even needed would allow for a safer, more efficient, and cost-effective approach. Under this model, patients would undergo genotyping upon hospital registration, with their test results seamlessly integrated into their medical record before prescriptions are considered.

One of the earliest trials to do just this was implemented in 2011 at St Jude Children’s Research Hospital in Memphis, Tennessee [13]. In this groundbreaking initiative, they opened a clinical research protocol called PG4KDS that established pre-emptive pharmacogenomic testing as a standard of care. PG4KDS examines 4,627 variants across 1,191 genes, and by June 2019, St. Jude had successfully integrated data from 11 genes and 35 drugs into their electronic health record (EHR) system for over 1,000 patients. This system enables clinicians to make informed decisions regarding high-risk medications, including the optimization of thiopurine dosing for leukemia patients [14] and guiding codeine use in pain management [15]. Notably, this system has expanded to several other leading children’s hospitals, including the Children’s Minnesota health-system and Boston Children’s Hospital [16].

This trial demonstrates that this type of genetic testing is feasible, clinically useful, and can be scaled to hospital settings. As sequencing becomes more accurate, cheaper, and faster, there is a huge potential for widespread genotyping, promising a future where tailored medications align perfectly with each individual’s genetic makeup.

A long time coming

According to the scientific journal, Nature, personalized medicine can be defined as a therapeutic approach involving the use of an individual’s genetic and epigenetic information to tailor drug therapy or preventive care [17]. This approach relies on the understanding of how a person’s unique molecular and genetic profile influences susceptibility to certain diseases and predicts which medical treatments will be safe and effective, and which ones will not. As such, it’s hard to deny that pharmacogenetics is at the heart of personalized medicine and will be essential to ensure that the treatments we provide will be effective and beneficial to each patient.

Over the last twenty years, the study of human genetics has been fueled by cutting-edge sequencing technologies leading to a deeper understanding of the relationship between genetic variation and human health.

At Eremid®, we are committed to delivering exceptional quality data and service in the pursuit of human health and longevity. As one of the most capable genomics laboratories in North America, our Genomics Services Lab integrates diverse NGS platforms (Illumina, ThermoFisher, 10x Genomics, Nanostring), supplemented by PacBio’s Revio long-read sequencing platform, to support highly accurate, affordable, and high-throughput studies of human health.

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2. Fang, H., Xu, X., Kaur, K., Dedek, M., Zhu, G., et al. (2019). A Screening Test for HLA-B∗15:02 in a Large United States Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00149
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