Tools and Challenges for the Implementation of Next-Generation Sequencing in Clinical Pharmacogenetics

Abstract

Understanding the genetic basis of an individual's response to therapeutic drugs (pharmacogenetics) is a unique area of research with significant translational impact for medicine. Known genetic variants with effects on important clinical phenotypes, including clopidogrel efficacy and warfarin maintenance dose, highlight the potential translational utility of pharmacogenetic analysis. Current strategies for clinical pharmacogenetic testing are primarily limited to genotyping of known, common variants. The emergence of next-generation sequencing offers a promising new tool to explore the links between drug response and genetic variation, both common and rare. The focus of my dissertation has been the application of next-generation sequencing technology to pharmacogenetic research and implementation. First, using exome sequence data from thousands of individuals, I demonstrate that novel, deleterious variation is common in key drug metabolizing enzymes among individuals of European and African descent, despite each variant being individually quite rare. I then use this same dataset to explore the inability of current pharmacogenetic nomenclature systems to accurately translate and represent results derived from exome sequencing. Finally, I present the development and testing of PGRNseq, a custom-capture platform designed for rapid, accurate detection of genetic variation within key pharmacogenes.