Maybe it’s Not the Drugs You Use; Maybe it’s Your Genes

Written by Manuel Seraydarian

Not any one individual is the same. Each individual has a genetic construct that is distinct from one another, whether it involves how fast your body can metabolize drugs, a defect in your DNA repair machinery which cannot reconstruct your DNA nucleotides accurately, or the subsequent inheritance of mutated BRCA1/BRCA2 breast cancer alleles, for example. These vast genetic characteristics are due to a myriad of “hot spot” genes that are known for their tendency to be polymorphic, or extremely variable [1]. Our genes control the fundamental proteins, known as enzymes, that are made for the purpose of regulating our bodies’ functions. Any enzyme that has reduced activity, no activity, or enhanced activity, as a result of inheriting or acquiring variations in our genes, directly affects our physiological complexion.

What is Pharmacogenomics?
Arno Motulsky, a medical geneticist, coined the term pharmacogenomics to illustrate the close correlation between an individual’s response to different drugs and dosages as a result of his or her specific genetic composition [2]. Each individual has various alleles and polymorphic changes in his or her genome, which is why patients have different reactions to certain drugs: whether it is beneficial, indifferent, or adverse and fatal.

Through pharmacogenomics, drug developers, physicians, and pharmacists can actively endeavor towards personalized medication as a method of clinical practice. Pharmaceutical companies can invest in drug development that would provide higher chances of benefiting patients by using patient response variability as a guide, instead of the costliness of the manufacturing of drugs that provide no valuable outcome. By having knowledge of a patient’s prior genetic history in medical records, physicians and pharmacists can prescribe the best drug and dosage selection for a patient, thus guaranteeing lower complications through an in vitro companion diagnostic test assay [3].

Medically, How are we Impacted?
Tailoring medication to an individual requires great diligence since all drugs that enter our bodies need to be metabolized by our liver and excreted as urine. Complications arise when polymorphic genes encode for non-functional enzymes or those with reduced activity that cannot metabolize drugs appropriately. Ineffective metabolism causes a buildup of toxicity due to the long-term presence of drugs within the body, resulting in adverse side effects and susceptibility to other diseases. For instance, ineffective metabolism of chemotherapeutic drugs allows the toxic metabolites to take root within other organs or block passage of blood vessels [3]. Metabolism of most drugs requires a range of Cytochrome P450 enzymes located within our liver, which consequently are targets of multiple variations. For instance, cytochrome CYP2D6 can have several polymorphisms, such as CYP2D6*1, CYP2D6*2, CYP2D6*3 and so on, with fully functional or non-functioning enzymes. Each person can be born with any of these variants and by chance, a drug might not be metabolized properly, leading to inimical effects. The only way to counter these effects is to reduce the dosage for partially functioning enzymes, increase the dosage for overly functioning enzymes, or change the drug for not functioning enzymes [4].

Tackling the Genetic Phenomenon
The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) started a nationwide project geared towards pediatric pharmacogenomics, Genetic Approach to Therapy in Children (GATC). This project supervises and inspects all adverse drug reactions in children and acquires DNA samples for genotyping, thus compiling it in medical records for locating a commonality in pharmacogenetics markers [5]. GATC acts as a framework for pharmaceutical companies to develop drugs tailored to these very commonly appearing allelic variants in a pediatric subgroup, and serves as a stepping stone towards personalized medication on a pediatric population level to provide for thousands at a time. Future projects can branch out to focus on specific polymorphic alleles that are depicted in appropriate patient subgroups, promoting a more organized effort to allow clinicians and pharmaceutical companies to tackle all these variants and prevent further side effects and fatalities.

References:

1. Pharmacogenomics. Pharmsci 163. Claudia Benavente “Pharmacogenetics in Drug Metabolism.” 19 January 2017.
2. “Arno Motulsky.” UW Genome Sciences: Arno Motulsky. N.p., n.d. Web. 06 Feb. 2017.
3. Relling, Mary V., and William E. Evans. “Pharmacogenomics in the Clinic.” Nature. U.S. National Library of Medicine, 15 Oct. 2015. Web. 28 Jan. 2017.
4. “Pharmacogenetics: The Right Drug for You.” Nature. U.S. National Library of Medicine, n.d. Web. 28 Jan. 2017.
5. “CYP2D6.” CYP2D6 – SNPedia. N.p., n.d. Web. 06 Feb. 2017.
6. Sing, Chor-Wing, Ching-Lung Cheung, and Ian C K Wong. “Pharmacogenomics – How Close/far Are We to Practising Individualized Medicine for Children?” British Journal of Clinical Pharmacology. BlackWell Publishing Ltd, Mar. 2015. Web. 28 Jan. 2017.