Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis.
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.
Channing Division of Network Medicine and.
Weiliang
W
Qiu
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford CA 94305-5236, USA.
Angela J
AJ
Rogers
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Amy
A
Damask
Channing Division of Network Medicine and Pulmonary Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA.
Benjamin A
BA
Raby
Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
Barbara J
BJ
Klanderman
Channing Division of Network Medicine and.
Qing Ling
QL
Duan
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford CA 94305-5236, USA.
Shiva
S
Tyagi
Channing Division of Network Medicine and.
Simin
S
Niu
Division of Immunology, and.
Christopher
C
Anderson
Translational Sciences, Virology/PML, Biogen Idec, Weston, MA 02493, USA.
Ellen
E
Cahir-Mcfarland
Division of Neonatology and Program in Pediatric Molecular and Personalized Medicine, Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
Thomas J
TJ
Mariani
Channing Division of Network Medicine and.
Vincent
V
Carey
Channing 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.
Kelan G
KG
Tantisira
D001741:Black or African American / Q000235:genetics; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016210:Methacholine Chloride / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000187:drug effects; D044465:White People / Q000235:genetics
D016210:Methacholine Chloride; D003907:Dexamethasone