Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII.
Wide variation in glucocorticoid (Gc) sensitivity exists between individuals which may influence susceptibility to, and treatment response of, inflammatory diseases. To determine a genetic fingerprint of Gc sensitivity 100 healthy human volunteers were polarized into the 10% most Gc-sensitive and 10% most Gc-resistant following a low dose dexamethasone (0.25 mg) suppression test. Gene expression profiling of primary lymphocytes identified the 98 most significantly Gc regulated genes. These genes were used to build a subnetwork of Gc signaling, with 54 genes mapping as nodes, and 6 non-Gc regulated genes inferred as signaling nodes. Twenty four of the 98 genes showed a difference in Gc response in vitro dependent on the Gc sensitivity of their donor individuals in vivo. A predictive model was built using both partial least squares discriminate analysis and support vector machines that predicted donor glucocorticoid sensitivity with 87% accuracy. Discriminating genes included bone morphogenetic protein receptor, type II (BMPRII). Transfection studies showed that BMPRII modulated Gc action. These studies reveal a broad base of gene expression that predicts Gc sensitivity and determine a Gc signaling network in human primary T lymphocytes. Furthermore, this combined gene profiling, and functional analysis approach has identified BMPRII as a modulator of Gc signaling.
Donn
Rachelle
R
Centre for Molecular Medicine, University of Manchester, Oxford Rd., Manchester, M13 9PT, UK.
Berry
Andy
A
Stevens
Adam
A
Farrow
Stuart
S
Betts
Joanna
J
Stevens
Richard
R
Clayton
Chris
C
Wang
Jixian
J
Warnock
Linda
L
Worthington
Jane
J
Scott
Laurie
L
Graham
Simon
S
Ray
David
D
D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D016000:Cluster Analysis; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D005938:Glucocorticoids; D003907:Dexamethasone; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II