title: Genetic variants contributing to daunorubicin-induced cytotoxicity.
abstract: Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity. A cell growth inhibition assay was used to measure variations in the cytotoxicity of daunorubicin. Gene expression was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. Using sequential analysis, we evaluated the associations between genotype and cytotoxicity, those significant genotypes with gene expression and correlated gene expression of the identified candidates with cytotoxicity. A total of 26, 9, and 18 genetic variants were identified to contribute to daunorubicin-induced cytotoxicity through their effect on 16, 9, and 36 gene expressions in the combined, Centre d' Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. Using 50 non-HapMap CEPH cell lines, single nucleotide polymorphisms generated through our model predicted 29% of the overall variation in daunorubicin sensitivity and the expression of CYP1B1 was significantly correlated with sensitivity to daunorubicin. In the CEPH validation set, rs120525235 and rs3750518 were significant predictors of transformed daunorubicin IC(50) (P = 0.005 and P = 0.0008, respectively), and rs1551315 trends toward significance (P = 0.089). This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
authors.forename: Shiwei
authors.initials: S
authors.lastname: Duan
authors.forename: Emily O
authors.initials: EO
authors.lastname: Kistner
authors.forename: Wasim K
authors.initials: WK
authors.lastname: Bleibel
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Donna L
authors.initials: DL
authors.lastname: Fackenthal
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003630:Daunorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000903:Antibiotics, Antineoplastic; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D003630:Daunorubicin