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

Qiu, W and Rogers, AJ and Damask, A and Raby, BA and Klanderman, BJ and Duan, QL and Tyagi, S and Niu, S and Anderson, C and Cahir-Mcfarland, E and Mariani, TJ and Carey, V and Tantisira, KG (2014) Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis. Human Molecular Genetics. pp. 5017-5024.

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 x 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

Item Type: Article
Additional Information: NIBR author: Damask, A institute: NIBR contributor address: Channing Division of Network Medicine and.
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23444

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