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

PLoS Genet. 2011 Jul;7(7):e1002162. doi: 10.1371/journal.pgen.1002162. Epub 2011 Jul 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes* / cytology
  • B-Lymphocytes* / drug effects
  • B-Lymphocytes* / metabolism
  • Cell Line, Transformed
  • Dexamethasone / pharmacology*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / drug effects
  • Genomics
  • Glucocorticoids* / metabolism
  • Glucocorticoids* / pharmacology
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Interleukin-6 / metabolism*
  • Italy
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Nigeria
  • Polymorphism, Genetic
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects*

Substances

  • APECED protein
  • Glucocorticoids
  • Immediate-Early Proteins
  • Interleukin-6
  • Receptors, Glucocorticoid
  • Transcription Factors
  • Dexamethasone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase