Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics

Pharmacogenetics represents "the study of variability in drug response due to heredity". Of the more than six dozen pharmacogenetic differences described in the medical literature, the majority of these variations occurs in drug-metabolizing enzyme genes and others in drug receptor and drug transporter genes, whereas many others have not yet been explained on a molecular basis. It is clear that "drug efficacy" or "drug toxicity" represents a multiplex phenotype, i.e. interaction between the drug (or its metabolites) and the gene products (enzymes, receptors, other targets) of two, and usually many more than two, genes. Because there is a gradient in these phenotypes (efficacy or toxicity), it is extremely important to select patients having the most unequivocal phenotype possible-if one wishes to find the gene(s) responsible for the trait. The method of "extreme discordant phenotype" (EDP) is therefore highly recommended. Using EDP methodology, DNA sequence variants (genotype) can be unconditionally correlated with drug efficacy or toxicity (phenotype). EDP methodology is mathematically intuitive and, in essence, has been used in a number of previous clinical pharmacogenetic studies. This EDP approach should be applicable to virtually any pharmaceutical agent in patient populations.