Genetic mapping with multiple levels of phenotypic information reveals determinants of lymphocyte glucocorticoid sensitivity.
Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (∼30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured in vitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4 × 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.
Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, 900 East 57(th) Street, Chicago, IL 60637, USA; Department of Human Genetics, The University of Chicago, 920 East 58(th) Street, Chicago, IL 60637, USA.
Joseph C
JC
Maranville
Shaneen S
SS
Baxter
David B
DB
Witonsky
Meredith A
MA
Chase
Anna
A
Di Rienzo
D000483:Alleles; D055106:Genome-Wide Association Study / Q000379:methods; D005938:Glucocorticoids / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000502:physiology; D008214:Lymphocytes / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome
D005938:Glucocorticoids; C405932:RBMS3 protein, human; D016601:RNA-Binding Proteins; D015534:Trans-Activators