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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Asthma / drug therapy
  • Asthma / genetics*
  • Black or African American / genetics
  • Cell Line
  • Child
  • Child, Preschool
  • Dexamethasone / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Humans
  • Methacholine Chloride / pharmacology*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci* / drug effects
  • White People / genetics

Substances

  • Methacholine Chloride
  • Dexamethasone