Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity
Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity
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DOI：
10.1186/1471-2164-15-292
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发表时间：
2014-04-16
期刊：
影响因子：
4.4
通讯作者：
Huang, Rong Stephanie
中科院分区：
文献类型：
--
作者：
LaCroix, Bonnie;Gamazon, Eric R.;Huang, Rong Stephanie
背景资料：利用全基因组遗传、基因表达和microRNA表达（miRNA）数据，我们开发了一种综合方法来研究化疗敏感性的遗传和表观遗传基础。通过一个连续的多阶段框架，我们鉴定了与铂敏感性相关的基因和miRNA，将其定位到基因组位点作为数量性状位点（QTL），并评估了这些QTL与铂敏感性之间的关联。排列分析表明，与传统药物敏感性GWAS的结果相比，我们方法的主要发现的错误发现率要低得多。我们的方法确定了与10个miRNAs相关的5个SNP和15个基因的表达水平，所有这些都与卡铂敏感性相关。特别令人感兴趣的是一个SNP（rs 11138019），其与miR-30 d和基因ABCD 2的表达相关，这两者本身与HapMap样品中的卡铂和顺铂药物特异性表型相关。功能研究发现，体外敲低ABCD 2导致顺铂处理后卵巢癌细胞系SKOV 3的凋亡增加。过表达的miR-30 d在体外引起的ABCD 2的表达减少，表明两者之间的功能relationship.Conclusions：我们开发了一种综合的方法来调查人类复杂性状的遗传和表观遗传基础。我们的方法优于标准GWAS，并提供了潜在生物功能的提示。ABCD 2和miR-30 d之间的关系，以及ABCD 2和铂敏感性的实验验证，表明ABCD 2和miR-30 d的铂剂的敏感性的功能作用。
Background: Using genome-wide genetic, gene expression, and microRNA expression (miRNA) data, we developed an integrative approach to investigate the genetic and epigenetic basis of chemotherapeutic sensitivity.Results: Through a sequential multi-stage framework, we identified genes and miRNAs whose expression correlated with platinum sensitivity, mapped these to genomic loci as quantitative trait loci (QTLs), and evaluated the associations between these QTLs and platinum sensitivity. A permutation analysis showed that top findings from our approach have a much lower false discovery rate compared to those from a traditional GWAS of drug sensitivity. Our approach identified five SNPs associated with 10 miRNAs and the expression level of 15 genes, all of which were associated with carboplatin sensitivity. Of particular interest was one SNP (rs11138019), which was associated with the expression of both miR-30d and the gene ABCD2, which were themselves correlated with both carboplatin and cisplatin drug-specific phenotype in the HapMap samples. Functional study found that knocking down ABCD2 in vitro led to increased apoptosis in ovarian cancer cell line SKOV3 after cisplatin treatment. Over-expression of miR-30d in vitro caused a decrease in ABCD2 expression, suggesting a functional relationship between the two.Conclusions: We developed an integrative approach to the investigation of the genetic and epigenetic basis of human complex traits. Our approach outperformed standard GWAS and provided hints at potential biological function. The relationships between ABCD2 and miR-30d, and ABCD2 and platin sensitivity were experimentally validated, suggesting a functional role of ABCD2 and miR-30d in sensitivity to platinating agents.