Dataset Information

Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines.

ABSTRACT: Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilized LCLs to perform association mapping for 29 chemotherapy drugs.Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European-Americans to 29 different anticancer drugs; the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose-response profiles between genotypes without making assumptions about the response curve or the biologic mode of association. Additionally, by classifying 25 of the 29 drugs into eight families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs.Among the single-drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in four additional suggestive loci (three contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family.This study demonstrates the utility of LCLs in identifying genes that have clinical importance in drug response and for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs.

SUBMITTER: Brown CC

PROVIDER: S-EPMC4055088 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines.

Brown Chad C CC Havener Tammy M TM Medina Marisa W MW Jack John R JR Krauss Ronald M RM McLeod Howard L HL Motsinger-Reif Alison A AA

Pharmacogenomics 20140201 2

<h4>Aim</h4>Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilized LCLs to perform association mapping for 29 chemotherapy drugs.<h4>Materials & methods</h4>Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European-Americans to 29 different anticancer drugs; the largest LCL study to date. A novel association approach using a multivariate analysis of cova ...[more]

PMID: 24444404

Similar Datasets

Project description:BackgroundExpression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.Methodology/principal findingsTo examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.Conclusions/significanceThis study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.

Dataset Information

Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines.

Publications

Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets