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Genetic Variants Contributing to Differences in Daunorubicin-induced Cytotoxicity

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Genetic Variants Contributing to Differences in Daunorubicin-induced Cytotoxicity

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    1. Genetic Variants Contributing to Differences in Daunorubicin-induced Cytotoxicity R. Stephanie Huang, Ph.D. University of Chicago

    2. Daunorubicin (DNR) Widely used in the treatment of leukemia, lymphoma and advanced HIV-associated Kaposi’s sarcoma Mechanism: Inhibition of DNA and RNA synthesis and interference with Top II activity Dose limiting toxicity -- myelosuppression and can cause cardiac toxicity

    3. Factors Contributing to Cytotoxicity

    4. Heritability Estimation for DNR

    5. Candidate Genetic Variants That May Contribute to The Sensitivity to DNR PK Metabolism enzymes Phase I: CYP2B1, CYP1A1 Phase II: GSTM1, GSTT1, GSTP1 Drug transporters MDR1,MRP1, MRP2, LRP PD TOP II Flt-1 ATM p53 p21 Rb BAX

    6. Objectives Develop a whole genome approach to identify genetic polymorphisms, expression patterns, and their combinations as predictors of DNR-induced cytotoxicities in various populations

    7. International HapMap Project To develop a haplotype map of the human genome and to describe the common patterns of human DNA sequence variation Extensive genotype data are available

    8. Phenotype EBV-transformed B-lymphoblastoid cell lines from thirty trios of healthy Yorubans and thirty trios of CEPH were utilized Cell growth inhibition experiments were conducted using a high-throughput alamarBlueTM assay

    11. Results

    12. Results

    13. Results

    15. rs3750518 Genotype, HNRPD Gene Expression and DNR IC50 in CEU Population

    16. rs6603859 Genotype, TAP2 Gene Expression and DNR IC50 in YRI Population

    17. Conclusions This novel genome-wide approach successfully integrated genotype, gene expression and sensitivity to drug information to identify genetic variants that are important in drug treatment Shed light on population specific genetic variants that contribute to DNR-induced toxicity It can be used to uncover important genetic variants contributing to a wide range of phenotypes that can be measured in lymphoblastoid cell lines

    18. What’s Next?

    19. Questions?

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