Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes.

Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
PLoS Genetics (Impact Factor: 8.52). 07/2011; 7(7):e1002162. DOI: 10.1371/journal.pgen.1002162
Source: PubMed

ABSTRACT Glucocorticoids (GCs) mediate physiological responses to environmental stress and are commonly used as pharmaceuticals. GCs act primarily through the GC receptor (GR, a transcription factor). Despite their clear biomedical importance, little is known about the genetic architecture of variation in GC response. Here we provide an initial assessment of variability in the cellular response to GC treatment by profiling gene expression and protein secretion in 114 EBV-transformed B lymphocytes of African and European ancestry. We found that genetic variation affects the response of nearby genes and exhibits distinctive patterns of genotype-treatment interactions, with genotypic effects evident in either only GC-treated or only control-treated conditions. Using a novel statistical framework, we identified interactions that influence the expression of 26 genes known to play central roles in GC-related pathways (e.g. NQO1, AIRE, and SGK1) and that influence the secretion of IL6.

  • [Show abstract] [Hide abstract]
    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 more than 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 2,484 cis-eQTL affecting 767 genes following dexamethasone treatment. A significant over-representation of lnPC20-associated cis-eQTL (190 SNPs) among differentially expressed genes (OR=1.76, 95% CI: 1.35-2.29) was noted in CAMP Caucasians. Forty-six of these 190 clinical associations were replicated in CAMP African Americans, including 7 SNPs near 6 genes meeting criteria for genome-wide significance (p<2x10(-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.
    Human Molecular Genetics 04/2014; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome-wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into 'functional' or 'non-functional', TFBS inputs to their target genes may be generally cumulative, with varying degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently 'spurious' sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome-wide association studies for complex traits.
    BioEssays : news and reviews in molecular, cellular and developmental biology. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have shown a large number of genetic variants to be associated with complex diseases. The identification of the causal variant within an associated locus can sometimes be difficult because of linkage disequilibrium between the associated variants and because most GWAS loci contain multiple genes, or no genes at all. Expression quantitative trait locus (eQTL) mapping is a method to determine the effects of genetic variants on gene expression levels. eQTL mapping studies have enabled the prioritization of genetic variants within GWAS loci, and have shown that trait-associated SNPs often function in a tissue- or cell type-specific manner, sometimes having downstream effects on completely different chromosomes. Furthermore, recent RNA-seq studies have shown that a large repertoire of transcripts is available in cells, which are actively regulated by (trait-associated) variants. Future eQTL mapping studies will focus on broadening the range of available tissues and cell types, in order to determine the key tissues and cell types involved in complex traits. Finally, large meta-analyses will be able to pinpoint the causal variants within the trait-associated loci and determine their downstream effects in greater detail. This article is part of a Special Issue entitled: From Genome to Function.
    Biochimica et Biophysica Acta 05/2014; · 4.66 Impact Factor

Full-text (3 Sources)

Available from
Jun 1, 2014