Pharmacogenomic discovery approaches: will the real genes please stand up?

Genetic inheritance plays a significant role in the interindividual variability of drug response. The field of pharmacogenomics seeks to identify genetic factors that influence drug response, including both those that are inherited and those that arise within tumors, and use this information to improve drug therapy. Candidate gene approaches have led to clinical tests for toxicity avoidance (eg, TPMT, UGT1A1) and efficacy prediction (eg, epidermal growth factor receptor-activating mutations).

CEPH individuals are representative of the European American population: implications for pharmacogenetics.

Previous studies have highlighted the use of phenotype generation in immortalized lymphoblastoid cells from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees as a powerful means of discovering genes involved in complex biological and pharmacological phenotypes. However, there is no data on how representative CEPH pedigrees are of the general population of European origin for genetic variants of pharmacogenetic significance. A vast amount of data in a population of restricted applicability would be of little value.

Genome-wide discovery of loci influencing chemotherapy cytotoxicity.

Little is known about the heritability of chemotherapy activity or the identity of genes that may enable the individualization of cancer chemotherapy. Although numerous genes are likely to influence chemotherapy response, current candidate gene-based pharmacogenetics approaches require a priori knowledge and the selection of a small number of candidate genes for hypothesis testing. In this study, an ex vivo familial genetics strategy using lymphoblastoid cells derived from Centre d'Etude du Polymorphisme Humain reference pedigrees was used to discover genetic determinants of chemotherapy cytotoxicity.