The world today is increasingly gravitating towards individuality than ever before, more and more accepting of the idea that a person’s response to a drug is biologically unique driven distinctly by their genetics. Pharmacogenomics investigates the variations in genetics on drug response and aims to improve the safety and effectiveness of drug treatment, inform prescription, and decision-making. Pharmacogenomics is the cornerstone of precision medicine or personalised medicine. German geneticist Friedrich Vogel coined the term ‘pharmacogenetics’ in 1959, dedicated to studying genetic variations in drug metabolic pathways impacting therapeutic effects and adverse effects. [1]

Polymorphism at the helm of pharmacogenomics
Despite prescriptions driven by age, weight, biochemical markers, and co-morbidities the number of patients who respond beneficially to a given drug varies between 25% to 80%, and adverse drug reaction (ADR) around 6% of all hospital admissions. [1, 2]
Variations in the human genome, also known as polymorphism can either be inherited or acquired. Changes in the genes, caused by polymorphism lead to variants or alleles, when it occurs in less than 1% of a population it is termed a mutation. Only a few mutations affect gene expression or the structure and therefore activity of the encoded protein. Gene expression is influenced by ‘epigenetics’, such as age, lifestyle, or disease. More than 97% of people carry at least one variant in a gene that can influence drug response by impacting the pharmacokinetics or pharmacodynamics of a drug. [1,2]

New age medications
Genes are responsible for absorption, distribution, metabolism, and excretion, including drug metabolism enzymes (cytochrome P450 isoforms, CYPs) and drug transporters. It is through knowledge of the drug’s pharmacology such as excessive drug activity through increased systemic exposure and or increased sensitivity of the target site to the drug leading to ADRs (hospital admission), that can be prevented. [3]

Cancer management is driven by new-age drugs that are targeted at patients with certain mutations. Vemurafenib was designed to inhibit V600E mutation in the BRAF gene in metastatic melanoma or trastuzumab in HER2-positive breast cancer. [1]

Environment influences CYP metabolic activity and drug response, but most of the CYP genes being polymorphic can result in different activity phenotypes. CYP2D6 can have four different activity phenotypes such as poor metabolizers, intermediate metabolisers, extensive metabolisers and ultra-rapid metabolizers. There may be 100 different CYP2D6 allelic variants that may have been recorded to date. About 6-10% of Caucasians are considered poor metabolisers, whereas less than 1% of Asians and 2-5% of African-Americans lack this enzyme. This enzyme is responsible for 25% of prescribed drugs. Ultra-rapid metabolizers phenotypes have been associated with fatal cases of opiate toxicity owing to rapid transformation to morphine. CYP1C19 is associated with clopidogrel activation and 3-5% of Caucasians and 12-23% of the Asian population are poor metabolisers. Hence pharmacogenomics provides valuable insights into underlying ADR mechanisms. [3]

Barriers to clinical adaptation
The completion of the Human Genome Project in 2003 is a milestone and the basis for mandates of a genetically literate primary care workforce by the Human Genetics Commission.[4] Pharmacogenomics spearheads this quantum shift but is hindered by a lack of evidence-based implementation guidelines and ethical issues surrounding genetic information that may concern patients and healthcare professionals. The lack of clear guidance on the requirements and consequences of testing continues to be a deterrent to many patients and healthcare professionals. Limitations of availability of equipment, trained personnel, and strict quality control procedures outside specialist units further impact the adaptation. There is poor uptake of testing owing to a deficit in prescriber knowledge surrounding translating genetic information into clinical action points. [5,6]

Future of Pharmacogenomics
The pharmacogenomics knowledge base provides a repository of drug-dosing clinical guidelines based on pharmacogenomics from multiple sources including the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenomics Working Group (DPWG). The US Pharmacogenomics Research Network (PGRN) has initiated the Translational Pharmacogenetics Program that aims to overcome barriers to pharmacogenomic testing in clinical practice. [7] Ubiquitous Pharmacogenomics Consortium (U-PGx) within Europe is the first large project that determines the impact of pre-emptive testing on ADR frequency, severity, and associated costs. [8] The pharmaceutical industry is moving from a blockbuster style of drug development into more expensive receptor or biomarker-targeted therapies.

Reference
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Meyer UA. Pharmacogenetics — five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 2004;5:669–676. doi: 10.1038/nrg1428
Serebruany V, Steinhubl SR, Berger PB et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45(2):246–251. doi: 10.1016/j.jacc.2004.09.067
National Human Genome Research Institute. All About The Human Genome Project (HGP). Available at: https://www.genome.gov/10001772/all-about-the–human-genome-project-hgp/ (accessed October 2017)
Kapoor R, Tan-Koi WC, Teo YY. Role of pharmacogenetics in public health and clinical health care: a SWOT analysis. Eur J Hum Genet 2016;24(12):1651–1657. doi: 10.1038/ejhg.2016.114
Haga SB, Burke W, Ginsburg GS et al. Primary care physicians’ knowledge of and experience with pharmacogenetic testing. Clin Genet 2012;82(4):388–394. doi: 10.1111/j.1399-0004.2012.01908.x
Shuldiner AR, Relling MV, Peterson JF et al. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: overcoming challenges of real-world implementation. Clin Pharmacol Ther 2013;94:207–210. doi: 10.1038/clpt.2013.59
van de Wouden CH, Cambon-Thomsen A, Cecchin E et al.; Ubiquitous Pharmacogenomics Consortium. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium. Clin Pharmacol Ther 2017;101(3):341–358. doi: 10.1002/cpt.602