The multigenic nature of sensitivity to drugs has limited the success of candidate gene approaches. We present a genome-wide model utilizing human lymphoblastoid cell lines from the International HapMap consortium, of which extensive genotypic information is available, to identify genetic variants that contribute to chemotherapeutic agent-induced cytotoxicity. Our model integrated genotype, gene expression and sensitivity of HapMap cell lines to drugs. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were utilized. Cell growth inhibition at increasing concentrations of chemotherapeutic agents (daunorubicin or etoposide) for 72 h was determined using alamarBlue® assay. Gene expression on 176 HapMap cell lines (87 CEU and 89 YRI) was determined using the Affymetrix GeneChip® Human exon 1.0 ST Array. SNP genotype and chemotherapeutic IC50 were linked through whole genome association in cell lines from both CEU and YRI populations. A second association test was performed between SNP genotype and gene expression and linear regression was utilized to evaluate the correlation between gene expression and drug IC50. Among the 387,417 SNPs tested, 207 and 49 SNPs were significantly associated with daunorubicin and etoposide-induced cytotoxicity, respectively (p < 0.0001). The expression of 17 and 3 genes whose expressions were significantly associated with SNP genotypes (Bonferroni corrected p < 0.05) were also correlated with daunorubicin or etoposide-induced cytotoxicity (p <0.05). Using our genome-wide approach, we identified 25 and 4 previously unknown genetic variants that contribute to daunorubicin or etoposide-induced toxicity through their effect on 17 and 3 gene expressions in the combined CEU and YRI populations. This novel, unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes induced by chemotherapeutic agents.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA