Pharmacogenomics: candidate gene identification, functional validation and mechanisms

Abstract

Pharmacogenetics is the study of the role of inheritance in variation in drug response phenotypes. Those phenotypes can range from life-threatening adverse drugs reactions at one end of the spectrum to equally serious lack of therapeutic efficacy at the other. Over the past half century, pharmacogenetics has--like all of medical genetics--evolved from a discipline with a focus on monogenetic traits to become pharmacogenomics, with a genome-wide perspective. This article will briefly review recent examples of the application of genome-wide techniques to clinical pharmacogenomic studies and to pharmacogenomic model systems that vary from cell line-based model systems to yeast gene deletion libraries. Functional validation of candidate genes and the use of genome-wide techniques to gain mechanistic insights will be emphasized for the establishment of biological plausibility and as essential follow-up steps after the identification of candidate genes.

Figure 1.

GWAS of statin-induced myopathy. (A) Association between myopathy and each SNP assayed in the GWAS. (B) Estimated cumulative risk of myopathy associated with 80 mg of simvastatin daily. (Modified from the SEARCH Collaborations Group (14) with permission of the Massachusetts Medical Society.)

Figure 2.

Diagramatic outline of the use of a cell line-based model system to identify and both functionally and clinically validate pharmacogenomic candidate genes.

Figure 3.

Functional validation of a candidate gene identified using the lymphoblastoid cell line model system. (A) siRNA knockdown of NT5C3 in cancer cell lines shifts the dose–response curves for AraC to the left, as anticipated. (B) Inverse correlation between NT5C3 mRNA levels and levels of AraC active metabolites in lymphoblastoid cells. (Modified from Li et al. (30) with permission of the American Association for Cancer Research.)