Drug target pharmacogenomics: an overview.

Abstract

Pharmacogenomics is a field aimed at understanding the genetic contribution to variability in drug efficacy and toxicity. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up. Pharmacogenetics has historically been a field focused primarily on genetic polymorphisms in drug metabolizing enzymes and their impact on drug efficacy and toxicity. More recently, investigators have begun to study the relationship between drug target polymorphisms and drug efficacy and toxicity. There are now numerous examples in the literature of associations between drug target polymorphisms and drug effect. Drug targets can be broken into three main categories: the direct protein target of the drug, signal transduction cascades or downstream proteins, and disease pathogenesis proteins. While the drug target pharmacogenetics literature provides 'proof of concept' that genetic variability contributes to the variability in drug response, the data are not to the point of being clinically useful in most cases. Specific problems to date include the inability of a single polymorphism to be highly predictive of response, and inconsistencies across studies of the same polymorphism. It seems likely that an important factor in the above limitations is the approach of focusing on a single polymorphism in a single gene. Given that most drug responses involve a large number of proteins, all of whose genes could have several polymorphisms, it seems unlikely that a single polymorphism in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it seems that a polygenic, or genomic approach will be more appropriate. Candidate gene and genome scanning approaches to pharmacogenomics have shown promise in relating drug target polymorphisms to response or toxicity, and pharmacogenomic strategies for drug discovery and drug development are now being implemented by most major pharmaceutical companies. Pharmacogenomics has the potential to significantly enhance the ability of clinicians to use medications in a safe and effective manner and, as such, represents an exciting field with tremendous clinical potential.