Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis.
Shukla, Sunita J. a; Duan, Shiwei b; Badner, Judith A. c; Wu, Xiaolin b; Dolan, M. Eileen b d e
Pharmacogenetics and Genomics.
18(3):253-262, March 2008.
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Objectives: Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.
Methods: Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.
Results: Significant heritability, ranging from 0.32 to 0.43 (P<10-7), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 [mu]mol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3-q35.2 (LOD=2.65, P=2.4x10-4) for 5 [mu]mol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P<=1x10-4). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatin-induced apoptosis.
Conclusions: Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.
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