Section of Genetic Medicine, Department of Medicine, University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA.
Genome Biol. 2011;12(5):R46. doi: 10.1186/gb-2011-12-5-r46. Epub 2011 May 25.
Recent studies have investigated the contribution of copy number variants (CNVs) to disease susceptibility in a multitude of complex disorders, including systemic lupus erythematosus, Crohn's disease, and various neurodevelopmental disorders. Relatively few CNV studies, however, have been conducted on pharmacologic phenotypes even though these structural variants are likely to play an important role. We developed a genome-wide method to identify CNVs that contribute to heterogeneity in drug response, focusing on drugs that are widely used in anticancer treatment regimens.
We conducted a comprehensive genome-wide study of CNVs from population-scale array-based and sequencing-based surveys by analyzing their effect on cellular sensitivity to platinating agents and topoisomerase II inhibitors. We identified extensive CNV regions associated with cellular sensitivity to functionally diverse chemotherapeutics, supporting the hypothesis that variation in copy number contributes to variation in drug response. Interestingly, although single nucleotide polymorphisms (SNPs) tag some of the CNVs associated with drug sensitivity, several of the most significant CNV-drug associations are independent of SNPs; consequently, they represent genetic variations that have not been previously interrogated by SNP studies of pharmacologic phenotypes.
Our findings demonstrate that pharmacogenomic studies may greatly benefit from the study of CNVs as expression quantitative trait loci, thus contributing broadly to our understanding of the complex traits genetics of CNVs. We also extend our PACdb resource, a database that makes available to the scientific community relationships between genetic variation, gene expression, and sensitivity to various drugs in cell-based models.
最近的研究已经调查了拷贝数变异（CNVs）在多种复杂疾病中的易感性的贡献，包括红斑狼疮、克罗恩病和各种神经发育障碍。然而，相对较少的 CNV 研究已经在药物表型上进行，尽管这些结构变异可能发挥重要作用。我们开发了一种全基因组方法来识别与药物反应异质性相关的 CNVs，重点是广泛用于癌症治疗方案的药物。
我们通过分析它们对铂类药物和拓扑异构酶 II 抑制剂细胞敏感性的影响，对基于群体规模的阵列和基于测序的调查中的 CNVs 进行了全面的全基因组研究。我们确定了与功能多样的化疗药物细胞敏感性相关的广泛的 CNV 区域，支持了这样的假设，即拷贝数的变异导致了药物反应的变异。有趣的是，尽管单核苷酸多态性（SNPs）标记了一些与药物敏感性相关的 CNVs，但几个最显著的 CNV-药物关联与 SNPs 无关；因此，它们代表了以前未通过 SNP 研究药物表型的遗传变异。
我们的发现表明，药物基因组学研究可能会从 CNVs 作为表达数量性状基因座的研究中受益匪浅，从而广泛促进我们对 CNVs 的复杂特征遗传的理解。我们还扩展了我们的 PACdb 资源，这是一个数据库，为科学界提供了遗传变异、基因表达和细胞模型中对各种药物敏感性之间的关系。
