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Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC) 50). In CEU lines, we tested 2 390 203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P< 0.001) and gene level (P< 0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC 50. The aspartate metabolism pathway was the most overrepresented among 199 pathways …