Mapping genes that contribute to daunorubicin-induced cytotoxicity.
Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity. Cell growth inhibition in 324 Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines (24 pedigrees) was evaluated following treatment with daunorubicin for 72 h. Heritability analysis showed a significant genetic component contributing to the cytotoxic phenotypes (h2 = 0.18-0.63 at 0.0125, 0.025, 0.05, 0.1, 0.2, and 1.0 mumol/L daunorubicin and at the IC50, the dose required to inhibit 50% cell growth). Whole-genome linkage scans at all drug concentrations and IC50 uncovered 11 regions with moderate peak LOD scores (> 1.5), including 4q28.2 to 4q32.3 with a maximum LOD score of 3.18. The quantitative transmission disequilibrium tests were done using 31,312 high-frequency single-nucleotide polymorphisms (SNP) located in the 1 LOD confidence interval of these 11 regions. Thirty genes were identified as significantly associated with daunorubicin-induced cytotoxicity (P < or = 2.0 x 10(-4), false discovery rate < or = 0.1). Pathway and functional gene ontology analysis showed that these genes were overrepresented in the phosphatidylinositol signaling system, axon guidance pathway, and GPI-anchored proteins family. Our findings suggest that a proportion of susceptibility to daunorubicin-induced cytotoxicity may be controlled by genetic determinants and that analysis using linkage-directed association studies with dense SNP markers can be used to identify the genetic variants contributing to cytotoxicity.
Duan
Shiwei
S
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Bleibel
Wasim K
WK
Huang
Rong Stephanie
RS
Shukla
Sunita J
SJ
Wu
Xiaolin
X
Badner
Judith A
JA
Dolan
M Eileen
ME
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D003630:Daunorubicin / Q000494:pharmacology*; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide
D000903:Antibiotics, Antineoplastic; D003630:Daunorubicin