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Hum Mol Genet. 2014 Sep 15;23(18):5017-24. doi: 10.1093/hmg/ddu191. Epub 2014 Apr 25.

Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis.

Author information

  • 1Channing Division of Network Medicine and.
  • 2Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford CA 94305-5236, USA.
  • 3Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
  • 4Channing Division of Network Medicine and Pulmonary Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA.
  • 5Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
  • 6Division of Immunology, and.
  • 7Translational Sciences, Virology/PML, Biogen Idec, Weston, MA 02493, USA.
  • 8Division of Neonatology and Program in Pediatric Molecular and Personalized Medicine, Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
  • 9Channing Division of Network Medicine and Pulmonary Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA kelan.tantisira@channing.harvard.edu.

Abstract

Nearly one-half of asthmatic patients do not respond to the most commonly prescribed controller therapy, inhaled corticosteroids (ICS). We conducted an expression quantitative trait loci (eQTL) analysis using >300 expression microarrays (from 117 lymphoblastoid cell lines) in corticosteroid (dexamethasone) treated and untreated cells derived from asthmatic subjects in the Childhood Asthma Management Program (CAMP) clinical trial. We then tested the associations of eQTL with longitudinal change in airway responsiveness to methacholine (LnPC20) on ICS. We identified 2484 cis-eQTL affecting 767 genes following dexamethasone treatment. A significant over-representation of lnPC20-associated cis-eQTL [190 single-nucleotide polymorphisms (SNPs)] among differentially expressed genes (odds ratio = 1.76, 95% confidence interval: 1.35-2.29) was noted in CAMP Caucasians. Forty-six of these 190 clinical associations were replicated in CAMP African Americans, including seven SNPs near six genes meeting criteria for genome-wide significance (P < 2 × 10(-7)). Notably, the majority of genome-wide findings would not have been uncovered via analysis of untreated samples. These results indicate that identifying eQTL after relevant environmental perturbation enables identification of true pharmacogenetic variants.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PMID:
24770851
[PubMed - in process]
PMCID:
PMC4140460
[Available on 2015/9/15]
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