The Rise of Pharmacogenomics and Personalised Medicine
When I was 16, I had my first ever surgery - a simple wisdom teeth removal. When I woke up, the doctors told me that apparently I had tried to wake up mid-surgery and even roll off the table.
I am also a redhead. Now these two facts may seem completely unrelated, but as we’ll soon see, maybe not.
The mechanism of action of many inhaled anaesthetics is unclear. Generally, anaesthetics like desflurane, isoflurane or sevoflurane act on inhibitory neurons, like NDMA, or excitatory neurons, like GABA, to induce a sleep-like, low pain state.
In a 2004 study from Liem, Ling and Suleman, they found a 19% increase in anaesthetic requirements in individuals with red hair compared to those with other hair colours.. The study also compared the genetic profiles to identify which commonly present mutations in redheads might be responsible for this. Specifically, the MCR1 gene is responsible for the creation and regulation of pigment, which contributes to the colouring of hair, nails and skin. Variants in this gene, most commonly seen in redheads, result in the decreased function of the MCR1 gene.
Now the correlation between the MCR1 gene, among others, and inhalational anaesthetics is still uncertain. But evidence suggests that three of the MCR1 alleles most commonly found in redheads are associated with decreased stimulation of intracellular cyclic AMP, an important secondary messenger in a number of cellular processes, when activated. Other evidence suggests that redheads have greater sensitivity to heat and cold pain, decreased effectiveness of lidocaine, and greater likelihood of melanoma. MCR1 receptors have also been identified in the brain and spinal cord, potentially playing a role in the amnesic and immobilising properties of inhaled anaesthetics.
Anecdotally, it’s been reported that redheads need up to 20% more anaesthetics. Unfortunately, this detail is not commonly known. This means that a lot of redheads report, not only resistance to anaesthetics, and chilling experiences like waking up mid-surgery, but also greater anxiety and fear towards surgical procedures. Admittedly, this phenomenon depends on the individual and the type of anaesthetic used, but nonetheless, it is pretty incredible.
The MCR1 gene is not the only gene that affects a body’s ability to process drugs. In fact, there is a whole emerging and fascinating field of pharmacogenomics.
Countless genes have effects on drugs. Some of them have a detrimental effect on a patient's health. Another example is with drugs used for leukaemia and other inflammatory diseases like thiopurine drugs. The enzyme Thiopurine Methyltransferase (TPMT) usually metabolises and inactivates the precursor drug 6-mercaptopurine. In a small number of people, they have certain genes that make this enzyme virtually non-existent. The effect of which is a disrupted balance of the active and inactive drug, and unacceptable toxicity of the drug. These days, TPMT levels are tested before someone is given thiopurine drugs, but this is just one example of many.
Pharmacogenomics plays, and will continue to play in the future, a key role in assessing potential efficacy of drugs, to a personalised degree. This makes sure that diseases are treated most effectively, and, when racial or sexual disparities are apparent. According to the CDC, African-Americans have statistically poor heart health outcomes, which has led researchers to investigate genetic factors, along socio-economic factors and bias. An example of genetic mutation that varies across racial identities is in the gene that codes for the enzyme Cytochrome P-450. It’s responsible for the metabolism of many drugs, including beta-blockers, like carvedilol, a drug class commonly used for high blood pressure and heart failure. Even more interesting, is that there is an allele of this gene, CYP2D6, which results in an impaired ability to metabolise these drugs. This allele is practically absent in White and Asian populations, but quite frequent in African American populations.
One day, genetic testing will be sophisticated and accessible enough to be able to routinely predict the effects of drugs on each individual person, and discrepancies between ethnic groups and sexes can be understood and better addressed within the healthcare field. But until then, it’s essential that genetic differences between different populations be studied and taught to all medical professionals, especially general practitioners and pharmacists. The possibilities of pharmacogenomics and personalised medicine are endless, and I personally am excited to see where it goes.
To learn more, check out:
Edwin B. Liem, Chun-Ming Lin, Mohammad-Irfan Suleman, Anthony G. Doufas, Ronald G. Gregg, Jacqueline M. Veauthier, Gary Loyd, Daniel I. Sessler; Anesthetic Requirement Is Increased in Redheads. Anesthesiology 2004; 101:279–283 doi: https://doi.org/10.1097/00000542-200408000-00006
Liem EB, Joiner TV, Tsueda K, Sessler DI. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology. 2005 Mar;102(3):509-14. doi: 10.1097/00000542-200503000-00006. PMID: 15731586; PMCID: PMC1692342.
National Human Genome Research Institute - 15 ways genomics influences our world https://www.genome.gov/dna-day/15-ways/pharmacogenomics