Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity

Abstract

Cytarabine arabinoside (ara-C) is an antimetabolite used to treat hematologic malignancies. Resistance is a common reason for treatment failure with adverse side effects contributing to morbidity and mortality. Identification of genetic factors important in susceptibility to ara-C cytotoxicity may allow for individualization of treatment. We used an unbiased wholegenome approach using lymphoblastoid cell lines derived from persons of European (CEU) or African (YRI) ancestry to identify these genetic factors. We interrogated more than 2 million single nucleotide polymorphisms (SNPs) for association with susceptibility to ara-C and narrowed our focus by concentrating on SNPs that affected gene expression. We identified a unique pharmacogenetic signature consisting of 4 SNPs explaining 51% of the variability in sensitivity to ara-C among the CEU and 5 SNPs explaining 58% of the variation among the YRI. Population-specific signatures were secondary to either (1) polymorphic SNPs in one population but monomorphic in the other, or (2) significant associations of SNPs with cytotoxicity or gene expression in one population but not the other. We validated the gene expressioncytotoxicity relationship for a subset of genes in a separate group of lymphoblastoid cell lines. These unique genetic signatures comprise novel genes that can now be studied further in functional studies.

Pharmacogenomic Discovery Using Cell-Based Models

“…Our laboratory found no relationship between EBV copy number or ATP levels and cellular sensitivity to drugs (A. L. Stark, W. Zhang, S. Mi, S. Duan, P. H. O'Donnell, R. S. Huang, M. E. Dolan, submitted). However, we did observe a significant correlation between cellular growth rate and sensitivity to chemotherapy that is not surprising, because many chemotherapeutic drugs are designed against rapidly growing cells (Huang et al, 2008c;Hartford et al, 2009). Therefore, genetic variants associated with sensitivity to chemotherapeutic agents may act through their association with growth rate.…”

“…Another phenotype to consider is measurement of conversion of parent drug to active metabolite. This has been effectively analyzed in the case of methotrexate glutamation (Masson et al, 1996) and the chemotherapeutic AraC, in which the amount of active metabolite (AraCTP) was associated with a specific genotype within an important drug-metabolizing gene (Hartford et al, 2009).…”

Population differences in microRNA expression and biological implications

“…Our group has previously observed in vitro population differences in cellular sensitivity to carboplatin, 25 daunorubicin 25 and araC 26 between the CEU and YRI samples. In this study, we evaluated whether differentially expressed miRNAs contribute to these observed ethnic differences in drug sensitivity.…”

“…We have reported in vitro population differences in cellular sensitivity to carboplatin, 25 daunorubicin 25 and araC 26 between the CEU and YRI samples. Cellular sensitivity to these chemotherapeutic agents-quantified by IC 50 (the concentration required to inhibit 50% of cell growth) for carboplatin and daunorubicin, along with AUC (area under the drug concentration cellular percent survival curve) for araC-was evaluated.…”

Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

“…Recent efforts have been aimed at using genome-wide approaches in pharmacogenomic discovery both in patients (4)(5)(6) and in cell-based models (7)(8)(9)(10)(11). The majority of genome-wide significant markers identified in patients through genome-wide association studies (GWASs) were for those rare but serious adverse events, such as the flucloxacillin-induced liver injury and statin-induced myopathy (5).…”