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

Area of Science:

• Pharmacogenetics
• Genomics
• Drug Discovery

Background:

• Pharmacogenetics of drug targets is emerging, distinct from drug metabolism.
• Polymorphisms in receptors and effector proteins demonstrably impact drug response variability.
• G protein coupled receptors (GPCRs) are key drug targets, with abundant genetic variation.

Purpose of the Study:

• To review the current status of drug target pharmacogenetics.
• To identify challenges hindering clinical application of genetic information in drug therapy.
• To highlight the importance of GPCRs in pharmacogenetic research.

Main Methods:

• Review of current pharmacogenetic literature focusing on drug targets.
• Analysis of G protein coupled receptors (GPCRs) and their polymorphisms.
• Illustration using beta-adrenergic receptor pharmacogenetic examples.

Main Results:

• GPCR genes exhibit higher rates of coding and nonsynonymous polymorphisms than other genes.
• Subtle functional effects of single polymorphisms limit predictive power for drug response.
• Inconsistencies across studies stem from sample size, phenotype definition, and focus on single nucleotide polymorphisms.

Conclusions:

• Clinical application of drug target pharmacogenetics requires larger studies addressing response complexity.
• Future research should incorporate multiple genes, haplotypes, and signal transduction pathways.
• Separate consideration of genetic contributions to drug response phenotypes is necessary for multi-target drugs.