A top-down, step up approach to pharmacogenetic discovery using CEPH family cell lines

Abstract

Background/Aims Previously Watters et al. (PNAS, 2004) found strong cell viability dose-response for 5-FU (0.21–0.70), and identified QTLs (chromosome 9: LOD=3.4) using public microsatellite data. We try to localize these toxicity genes using the HapMap published SNPs. Methods 30 CEPH HapMap trio cell lines, treated with 9 different doses of 5-FU, were analyzed at 4928 SNPs in the chromosome 9 QTL region. We used various statistical methods (179 SNPs were significant at p<0.05, uncorrected), including the False Discovery Rate, Storey's Q, and Sequential Multiple Decision Procedures (SMDP). Results Five SNPs were chosen as significant signals by SMDP at a power of 95% (but requiring only 78% of the sample), with sequential R2 of 0.16, 0.16, 0.17, 0.17, 0.11 respectively. Subselecting LD tag SNPs (Lazarus et al., 2004) reduces the number by nearly half, thus improving power. We employ a step up strategy from single SNPs to LD blocks to haplotypes, and finally to gene-based associations. Conclusions CEPH family cell lines are a powerful, unique resource for in vitro phamacogenetic toxicity gene discovery. Clinical Pharmacology & Therapeutics (2005) 77, P8–P8; doi: 10.1016/j.clpt.2004.11.031