Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity - PubMed (original) (raw)
Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity
Christine M Hartford et al. Blood. 2009.
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 whole-genome 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 expression-cytotoxicity 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.
Figures
Figure 1
Cytotoxicity of ara-C in CEU and YRI populations. (A) The mean percentage survival in the CEU compared with the YRI cell lines was 73.3 versus 70.5 at 1 μM (P = .24), 53.3 versus 47.3 at 5 μM (P = .002), 46.8 versus 39.9 at 10 μM (P = 1 × 10−4), 40.3 versus 32.8 at 40 μM (P < 1 × 10−4), and 37.3 versus 30.4 (P < 1 × 10−4) at 80 μM ara-C. (B) The distribution of log2 AUC in CEU and YRI cell lines (P < 1 × 10−4).
Figure 2
Analysis of DCK expression. (A) Distribution of DCK mRNA expression measured on the Affymetrix GeneChip Human Exon 1.0 ST array in the CEU and YRI cell lines (P = .02). (B) Association between level of DCK protein expression and log2 AUC in a subset of YRI cell lines (r2 = 0.69, P = .04). (C) Association between DCK SNP genotype and log2 AUC (P = .02), DCK expression levels (P = .003), and intracellular ara-CTP (P = .003).
Figure 3
SNP rs17808412 and GIT1. In the CEU population, rs17808412 demonstrated a significant association between SNP genotype and both (A) ara-C AUC (P = 1 × 10−5) and (B) the level of expression of GIT1 (P = 1 × 10−6). (A,B) In the YRI population, this SNP is not variable, with all cell lines having the (GG) genotype. (C) Expression of GIT1 and AUC was significantly correlated in the CEU population (r2 = 0.200, P = 7 × 10−5). (D) This correlation was validated in an independent set of CEU cell lines.
Figure 4
rs10973320 and RAD51AP1. rs10973320 demonstrated genetic variability in the YRI population as well as an association between genotype and both (A) AUC (P = 2 × 10−5) and (B) expression of RAD51AP1 (P = 4 × 10−8). (A,B) This SNP is not variable in the CEU population. (C) Expression of RAD51AP1 and AUC were significantly correlated in the YRI population.
Figure 5
rs2775139 and SLC25A37. rs2775139 is variable in both CEU and YRI cell lines. In the CEU cell lines, genotype is associated with both (A) AUC (P = 8 × 10−6) and (B) expression of SLC25A37 (P = 1 × 10−6). Among the YRI cell lines, all genotypes demonstrate similar (A) AUC and (B) SLC25A37 expression. (C) Expression of SLC25A37 and AUC was significantly correlated in the CEU population (r2 = 0.169, P = 7 × 10−4). (D) This association was validated in an independent set of CEU cell lines in which AUC significantly correlated with expression of SLC25A37 (r2 = 0.0817, P = .05).
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