title: Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity.
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.
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaCroix
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Divya
authors.initials: D
authors.lastname: Lenkala
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: Paul
authors.initials: P
authors.lastname: Geeleher
authors.forename: Dana
authors.initials: D
authors.lastname: Ziliak
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, 900 E 57th street, KCBD room 7148, Chicago, IL, 60637, USA. rhuang@medicine.bsd.uchicago.edu.
authors.forename: Rong Stephanie
authors.initials: RS
authors.lastname: Huang
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D010641:Phenotype; D010984:Platinum / Q000494:pharmacology*; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D010984:Platinum
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