Ex-Vivo Modeling for Heritability Assessment and Genetic Mapping in Pharmacogenomics.

Abstract

The investigation of genetic factors that determine differential drug response is a key goal of pharmacogenomics (PGX), and relies on the often-untested assumption that differential response is heritable. While limitations in traditional study design often prohibit heritability (h²) estimates in PGX, new approaches may allow such estimates. We demonstrate an ex vivo model system to determine the h² of drug-induced cell killing and performed genome-wide analysis for gene mapping. The cytotoxic effect of 29 diverse chemotherapeutic agents on lymphoblastoid cell lines (LCLs) derived from family- and population-based cohorts was investigated. We used a high throughput format to determine cytotoxicity of the drugs on LCLs and developed a new evolutionary computation approach to fit response curves for each individual. Variance components analysis determined the h² for each drug response and a wide range of values was observed across drugs. Genome-wide analysis was performed using new analytical approaches. These results lay the groundwork for future studies to uncover genes influencing chemotherapeutic response and demonstrate a new computational framework for performing such analysis.