Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges.

The pharmacogenetics literature of drug receptors and effector proteins is in its relative infancy compared to that of drug metabolism pharmacogenetics. Nonetheless, in a short time period, numerous studies have demonstrated that receptor/effector polymorphisms contribute to variable drug response. We review the current status, and list challenges that confront drug target pharmacogenetics before we can use genetic information in drug-therapy decision-making. We focus our review on G protein coupled receptors (GPCRs), which represent over 50% of all drug targets, and use specific examples from the beta-adrenergic receptor pharmacogenetic literature to illustrate important issues. Recent resequencing efforts of GPCR genes suggest that they have more coding region and nonsynonymous polymorphisms than non-GPCR genes, thus making GPCRs important foci for pharmacogenetic investigation. Our inability to use drug target genetic information to guide in the selection of drug therapy is due to several factors, including (i) the relatively subtle functional effects of the single gene polymorphisms, which do not account for enough of the drug response variability to accurately predict response and (ii) inconsistencies between studies. The latter may be due to some studies having inadequate sample sizes, studying different drug response phenotypes and patient populations, difficulties in identifying and measuring a valid drug response phenotype, and focusing on single polymorphisms in single genes, rather than haplotypes or multiple genes. To move the field to the point of clinical application, future studies will need to be larger, and will have to consider the complexity of the drug response, either by inclusion of polymorphisms from signal transduction proteins and other proteins relevant to the drug response, or through a genomics approach. Finally, the literature suggests that, for those drugs with multiple pharmacologic effects, or effects in multiple organs, the genetic contribution to each drug response phenotype will have to be considered separately. The knowledge necessary to move forward on all these fronts is not yet available, but will be increasingly accessible over the next few years.