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A Personalized Approach to Healthcare
Precision medicine is a term that has superseded the older term of “personalized medicine”. Both terms refer to a medical approach that takes into account an individual’s genetic variations, environment and lifestyle in order to prescribe treatments and preventative care. This approach improves patient outcomes by tailoring the treatment at the right time in the correct amounts.
Genetic variations in expression of receptors and enzymes may result in differing responses to medical treatments. Likewise, lifestyle differences can alter treatment responses. Examples of lifestyle differences include exercise, diet, drinking or smoking. For a long time, lifestyle differences were rather easy to identify. However, lifestyle changes were always up to the individual. A more difficult task was identifying genetic variations other than from family history. We now live in an era where genetic services exist to identify variations.
The Role of Genetics in Precision Medicine
Some of our personal preferences arise from the way we were brought up. Culture plays a role in our likes and dislikes. Likewise, our experiences play a role in how we respond to certain stimuli. Another major factor that plays a role into our preferences comes wired in our genome. The DNA in our cells is the instruction manual for who we are. We are programmed to seek out things of a nutritive values in order to acquire raw materials like carbohydrates, proteins and lipids. In our search for nutritive compounds we have learned to avoid things that don’t taste good. Bitter things have a tendency to be associated with toxic compounds in nature. When eating a food item for the first time, molecules hit our tongue and stimulate multiple sensations: sweet, sour, salty, savory and bitter. Attributed to these multiple taste types are a diverse family of receptors that bind to the molecules that result in our perception of these sensations. Something bitter might make us learn to avoid this food item in the future.
One type of bitter receptor senses the presence of a chemical called phenylthiocarbamide (PTC). This chemical chemically resembles toxic compounds found in plants but is non-toxic. The ability to taste PTC is comes from the gene called TAS2R38. This gene encodes a protein that on our tongues that communicates the bitterness of this chemical. There are two common alleles of this gene with at least five more uncommon variants. Within the two common forms, a single nucleotide polymorphism (SNP) is responsible for changing one amino acid in the receptor. It’s this difference of one amino acid that results in the ability of the receptor to either respond or not respond to PTC. We inherit one copy of the gene from our father and one copy from our mother. Based on how our parents gametes were formed and what alleles we received during the fertilization event determines how we respond to this chemical. Because we each have 2 copies of this gene, we can utilize simple Mendelian genetics to understand which allele is dominant or recessive.
Utilizing an assay called derived Cleaved Amplified Polymorphic Sequences (dCAPS), the partial DNA for the location of the SNP is made. The primer used in amplifying this region contains an intentional mismatch that will create a restriction site for one of the alleles. By using a restriction enzyme to digest at this site, it can be revealed what alleles exist that correspond to the phenotype observed.
Case Study: Red Hair and Altered Pain Response
The MC1R gene
International Redhead Day 2011 – by Qsimple
The Melanocortin 1 Receptor gene (MC1R) encodes a protein that responds to the hormone known as melanocortins. This signal stimulates the production of eumelanin, a dark brown or black pigment. Mutations in this receptor is faulty at stimulating the eumelanin production and shifts to the production of a reddish-yellow pigment called pheomelanin. Individuals with functional MC1R can produce eumelanin and display darker pigments in the skin and hair. Genetic variants in this gene strongly associated with red hair are known as rs1805007 (R151C) and rs1805008 (R160W).
Several studies have reported that redheads may require higher doses of anesthesia compared to individuals with other hair colors. These genetic changes have been verified in mice carrying the red-hair variants and their responsiveness to specific types of pain stimuli (Mogil et al., 2003; Mogil et al., 2005; Robinson et al., 2021).
rs1805007 (R151C)
| Genotype | Hair Color | Melanoma Risk | Analgesic effect |
| CC | Non-red hair | Normal risk | |
| CT | Red hair carrier | Higher risk | |
| TT | 13-20x higher likelihood of red hair | High risk | Increased response* |
*The R151C has been linked to being increased responsiveness to the analgesics pentazocine, nalbuphine, and butorphanol but also demonstrated decreased responsiveness to inhaled general anesthesia desflurane. This variant is associated with increased κ-opioid agonism (female specific).
rs1805008 (R160W)
| Genotype | Hair Color | Melanoma Risk |
| CC | Non-red hair | Normal risk |
| CT | Red hair carrier | Higher risk |
| TT | ~7-10x higher likelihood of red hair | Higher risk |
Associated with increased analgesic responsiveness to κ-opioid agonism (female specific).
Case Study: Warfarin Sensitivity
Originally a rat poison, warfarin is a common anticoagulant medication used to prevent blood clots through the inhibition of the enzyme vitamin K epoxide reductase (VKORC1). This is particularly important to prevent deep-vein thrombosis and pulmonary embolisms.
Vitamin K is involved in activating clotting factors in the blood. VKORC1 enzyme is responsible for the recycling of the Vitamin K1. Reduction in activity results in the inability to effectively form blood clots and increases bleeding. 
Reactivation of Vitamin K1 VKOR. Credit: J3D3 (CC BY-SA 4.0)Enzymes in the Cytochrome P450 family are responsible in metabolism of drugs and chemicals. The specific Cytochrome P450 gene involved in breaking down warfarin is the CYP2C9. Clinical variants in VKORC1 and CYP2C9 have been identified that result in warfarin sensitivity. The VKORC1 variant -1639G>A (rs9923231) contains a SNP in the promoter and is thought to reduce the expression of the enzyme. CYP2C9*2 and CYP2C9*3 are variants of CYP2C9 that result in missense mutations where the metabolism of warfarin is drastically reduced, leading to the extended presence of the chemical and continued inhibition of VKOR activity.
| Gene | Variant outcome | SNP ID | Warfarin Sensitivity |
| VKORC1 | -1639G>A | rs9923231 | Increased sensitivity, lower dose required |
| CYP2C9 (variant*2) | R144C | rs1799853 | Decreased metabolism, lower dose required |
| CYP2C9 (variant *3) | I359L | rs1057910 | Decreased metabolism, lower dose required |
Case Study: The Royal Disease
Hemophilia B, a rare X-linked recessive bleeding disorder. The fascinating history of this disease is exemplified by the Victorian and Romanov families earning it the nickname of the “Royal Disease”.
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Case Presentation
- Patient: Alexei Nikolaevich Romanov, Tsesarevich of Russia
- Age: 13 years old (12 August 1904-17 July 1918)
- Chief Complaint: Recurrent, severe bleeding episodes
Hemophilia in Queen Victoria’s descendents. Credit: [[Useravablack.hrek]] (CC BY-SA 4.0)
Alexei was the great grandson of Queen Victoria through his mother, Alexandra Feodorovna (Alix of Hesse and by Rhine). He presented with frequent and severe bleeding episodes throughout his life. After his umbilical cord was cut, his navel continued to bleed for several hours. His frequent bleeding episodes significantly impacted his quality of life and limited his physical activity.
Family History
- Maternal Lineage:
- Queen Victoria of England: Carrier of the hemophilia B gene
- Tsarevna Alexandra Feodorovna: Carrier of the hemophilia B gene
- Paternal Lineage:
- Tsar Nicholas II of Russia: Not a carrier of the hemophilia B gene
Genetic Basis of Alexei’s Hemophilia
In 2009, Evgeny Rogaev examined the DNA from a body identified as Alexei. From this DNA, the group searched for mutations in a gene called F8 (Factor VIII), which results in hemophilia A. When this highly prevalent (greater than 80% cases) form of hemophilia was not determined, the group searched through the F9 (Factor IX) gene. A SNP in an intron of F9 (rs398122990) was found indicating that hemophilia B (Plasma Thromboplastin Component Deficiency) was the royal form of the disease (Rogaev et al, 2009). Both F8 and F9 are located on the X-chromosome (q28 and q27.1, respectively).
Impact of Hemophilia B on Alexei Romanov
- Physical Limitations: Frequent bleeding episodes led to joint damage, pain, and reduced mobility.
- Psychological Impact: The chronic nature of the disease and the fear of bleeding episodes affected Alexei’s emotional well-being.
- Medical Management: Limited treatment options were available at the time, leading to significant morbidity and mortality.
Modern Management of Hemophilia B
- Factor IX Replacement Therapy: Regular infusions of recombinant factor IX can significantly improve the quality of life for individuals with hemophilia B.
- BeneFIX, Rebinyn, Rixubis, Idelvion, Alprolix, Refixia
- Prophylactic Treatment: Regular prophylactic infusions can prevent spontaneous bleeding episodes.
- Gene Therapy: Ongoing research aims to develop gene therapy as a potential cure for hemophilia B.
Conclusion
The case of Alexei Romanov highlights the devastating impact of hemophilia B on individuals and families. By understanding the genetic basis of the disease and advancements in treatment, healthcare providers can offer effective management and improve the lives of those affected by hemophilia B.
Role of the Nurse in Precision Medicine
- Implications for Drug Development and Prescription:
- Tailoring drug dosages and treatment plans based on genetic information.
- Identifying individuals at risk for adverse drug reactions.
- Developing personalized medicine strategies.
- Genetic Testing: Nurses can educate patients about the benefits of genetic testing and assist in obtaining necessary samples.
- Medication Administration: Nurses can administer warfarin based on individualized dosing recommendations.
- Monitoring: Nurses can monitor patients closely for signs of bleeding or clotting, adjusting dosages as needed.
- Patient Education: Nurses can educate patients about the importance of adherence to medication regimens, potential side effects, and the need for regular blood tests to monitor warfarin levels.
The Future of Precision Medicine
- Challenges and Limitations:
- Ethical considerations, cost-effectiveness, and data privacy.
- Need for large-scale genomic studies and advanced bioinformatics tools.
- Potential Benefits:
- Improved patient outcomes, reduced healthcare costs, and accelerated drug development.
- Conclusion:
- Precision medicine holds the promise of revolutionizing healthcare by providing targeted treatments for individual patients.
- By understanding the genetic basis of individual differences, we can move towards a future of more effective and personalized medicine.
