Evolution of Pharmacogenomics

Abstract

Pharmacogenetics dates back more than 2,000 years to observations by Pythagoras, however it was not until the 1950s when some enzyme polymorphisms (e.g., N-acetyltransferase, G6PD) were discovered that the term was coined by Vogel. Pharmacogenetics then went into decline as being too esoteric a subject. In the 1970s the discovery of the CYP2D6 polymorphism and its resultant effect on drug toxicity and response led to many observations of pharmacogenetic-based variations in pharmacokinetics. These and other discoveries and the subsequent ability to genotype led to the term pharmacogenomics. Today, there are an increasing number of genes for which polymorphisms have been identified that are associated with variable drug response whether it be at the drug metabolizing enzyme, transporter or receptor level and, mainly through a candidate genes(s) approach. Increasing use of genome-wide analysis is identifying hitherto unpredictable new genes associated with disease and drug response. Although some old and most new drugs coming onto the market have a “pharmacogenomic footprint”, the clinical and practical usefulness of pharmacogenomics has been generally lacking. To date, clinical translation of pharmacogenetics has focused on narrow therapeutic index drugs for toxicity (e.g., azathioprine) and more recently for efficacy and toxicity (e.g., warfarin) purposes. Pharmacogenetics and genomics will be advanced through lower cost, rapid whole genome sequencing methods combined with sophisticated algorithms allowing individualised dosage recommendations but not necessarily their adoption. However, complicating this is the influence of changes in gene expression by environmental and genetic factors. Therefore translation of pharmacogenetics into “personalised medicine” will depend on many factors including clinical relevance, environmental-genetic interactions, cost and education.