Mapping genes that contribute to daunorubicin-induced cytotoxicity.

Mapping genes that contribute to daunorubicin-induced cytotoxicity. Research Abstract Details 

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Mapping genes that contribute to daunorubicin-induced cytotoxicity. Abstract Text:

Shiwei Duan,Wasim K Bleibel,Rong Stephanie Huang,Sunita J Shukla,Xiaolin Wu,Judith A Badner,M Eileen Dolan,

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.

Mapping genes that contribute to daunorubicin-induced cytotoxicity. Publishing Authors By Initials

S Duan,WK Bleibel,RS Huang,SJ Shukla,X Wu,JA Badner,ME Dolan,

For similar genetic phenomena: variation (genetics): polymorphism, genetic: polymorphism, single nucleotide research abstracts see: genetic phenomena: variation (genetics): polymorphism, genetic: polymorphism, single nucleotide research

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Mapping genes that contribute to daunorubicin-induced cytotoxicity. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 67

Page Numbers: 5425-33

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 1

MONTH: Jun

YEAR: 2007

Mapping genes that contribute to daunorubicin-induced cytotoxicity. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Mapping genes that contribute to daunorubicin-induced cytotoxicity. Keywords Mesh Terms:

KEYWORDS: Polymorphism, Single Nucleotide

MESH TERMS: physiology

Chemical & Substance for Abstract: Mapping genes that contribute to daunorubicin-induced cytotoxicity. Information

Substance Name: Daunorubicin

Registry Number: 20830-81-3

Grant and Affiliation Information for Mapping genes that contribute to daunorubicin-induced cytotoxicity.

AFFILIATION: Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: U01GM61374

ACRONYM: GM

MEDLINETA: Cancer Res

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