Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 23, Pages 9758-9763Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0703736104
Keywords
HapMap; pharmacogenomics; toxicity; whole-genome association
Categories
Funding
- NIGMS NIH HHS [U01 GM061374, U01 GM061393, U01GM61374, GM61393] Funding Source: Medline
Ask authors/readers for more resources
Large interindividual variance has been observed in sensitivity to drugs. To comprehensively decipher the genetic contribution to these variations in drug susceptibility, we present a genome-wide model using human lymphoblastoid cell lines from the International HapMap consortium, of which extensive genotypic information is available, to identify genetic variants that contribute to chemotherapeutic agent-induced cytotoxicity. Our model integrated genotype, gene expression, and sensitivity of HapMap cell lines to drugs. Cell lines derived from 30 trios of European descent (Center d'Etude du Polymorphisme Humain population) and 30 trios of African descent (Yoruban population) were used. Cell growth inhibition at increasing concentrations of etoposide for 72 h was determined by using alamarBlue assay. Gene expression on 176 HapMap cell lines (87 Center d'Etude du Polymorphisme Humain population and 89 Yoruban population) was determined by using the Affymetrix GeneChip Human Exon 1.0ST Array. We evaluated associations between genotype and cytotoxicity, genotype and gene expression and correlated gene expression of the identified candidates with cytotoxicity. The analysis identified 63 genetic variants that contribute to etoposide-induced toxicity through their effect on gene expression. These include genes that may play a role in cancer (AGPAT2, IL1B, and WNT5B) and genes not yet known to be associated with sensitivity to etoposide. This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes induced by chemotherapeutic agents.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available