Open Access Methodology article

Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity

Bonnie LaCroix1, Eric R Gamazon2, Divya Lenkala1, Hae Kyung Im23, Paul Geeleher1, Dana Ziliak1, Nancy J Cox2 and Rong Stephanie Huang1*

Author Affiliations

1 Section of Hematology/Oncology, Department of Medicine, University of Chicago, 900 E 57th street, KCBD room 7148, Chicago, IL, 60637, USA

2 Section of Genetic Medicine, Department of Medicine, Chicago, IL, 60637, USA

3 Department of Health Studies, The University of Chicago, Chicago, IL, 60637, USA

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BMC Genomics 2014, 15:292  doi:10.1186/1471-2164-15-292

Published: 16 April 2014

Abstract

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.

Keywords:
microRNA; Gene expression; SNP; Platinum; HapMap