title: Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes.
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.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Maranville
authors.forename: Francesca
authors.initials: F
authors.lastname: Luca
authors.forename: Allison L
authors.initials: AL
authors.lastname: Richards
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Wen
authors.forename: David B
authors.initials: DB
authors.lastname: Witonsky
authors.forename: Shaneen
authors.initials: S
authors.lastname: Baxter
authors.forename: Matthew
authors.initials: M
authors.lastname: Stephens
authors.forename: Anna
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D003907:Dexamethasone / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007558:Italy; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009549:Nigeria; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D000096927:AIRE Protein; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D016660:NAD(P)H Dehydrogenase (Quinone); D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000096927:AIRE Protein; D000099184:Serum-Glucocorticoid Regulated Kinases; C447479:NQO1 protein, human