CREATE Abstract, 2000
Functional Polymorphism Analysis in Drug Pathways
Most pharmacogenetic strategies to date have focused on the role of single genes in the regulation of drug activity and have made important steps towards the goal of optimizing therapy for individual patients. However, there is clear evidence that medications, like most common diseases, are under the control of a network of genes, each contributing to the patient's phenotype. The CREATE Pharmacogenetic Research Network (Comprehensive Research on Expressed Alleles in Therapeutic Evaluation) will bring together infrastructure for the evaluation of pathways regulating drug activity. This will be achieved through the coordinated efforts of investigators from Washington University and University of California, San Francisco with expertise in the fields of Genomics, Pharmacogenetics, Clinical Pharmacology, BioinformaticsfComputational Biology, Molecular Genetics, Statistical Genetics, Population Genetics, Clinical Trials, and Translational Research. Together they will evaluate the following general aims to develop validation strategies for applied pharmacokinetics.
General aims:
- Identify polymorphisms in genes that are components of pathways regulating drug activity;
- Determine the genotype-expression relationship in therapeutically relevant tissue;
- Establish the population characteristics of polymorphisms in Caucasian, Hispanic, Asian, and African American subjects; and,
- Provide clinical validation of polymorphisms in pathways regulating drug activity.
These aims will be achieved using human gastrointestinal cancer as a model system, as it is a common cause of death, has no clear prognostic tools to guide therapy, has ethnic differences in incidence and outcome, has readily accessible tissue available in the Tissue Procurement Core facilities, and is treated with a small number of medications (three drugs). Defined gene pathways are clear for these agents and the Network will identify and evaluate variants in 124 genes to evaluate a comprehensive approach to pharmacogenetics.