Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity
Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity
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DOI：
10.1182/blood-2008-05-154302
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发表时间：
2009-03-05
期刊：
影响因子：
20.3
通讯作者：
Dolan, M. Eileen
中科院分区：
文献类型：
--
作者：
Hartford, Christine M.;Duan, Shiwei;Dolan, M. Eileen
阿糖胞苷（ara-C）是一种用于治疗血液恶性肿瘤的抗代谢物。耐药性是治疗失败的常见原因，其不良副作用会导致发病率和死亡率。鉴定对ara-C细胞毒性易感性重要的遗传因素可能允许个体化治疗。我们使用了一种无偏倚的全基因组方法，使用来自欧洲人（CEU）或非洲人（YRI）血统的淋巴母细胞样细胞系来确定这些遗传因素。我们调查了超过200万个与ara-C易感性相关的单核苷酸多态性（snp），并通过集中研究影响基因表达的snp来缩小我们的研究范围。我们确定了一个独特的药理学特征，由4个snp组成，解释了CEU中对ara-C敏感性的51%的变异，5个snp解释了YRI中58%的变异。群体特异性特征是继发于(1)在一个群体中多态snp而在另一个群体中单态snp，或者(2)在一个群体中snp与细胞毒性或基因表达有显著关联，而在另一个群体中则没有。我们在一组单独的淋巴母细胞细胞系中验证了基因表达与细胞毒性的关系。这些独特的遗传特征组成了新的基因，现在可以在功能研究中进一步研究。（Blood. 2009; 113: 2145-2153）
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. (Blood. 2009; 113: 2145-2153)