Glucocorticoid gene signatures in systemic lupus erythematosus and the effects of type I interferon: a cross-sectional and in-vitro study. (May 2021)

• Record Type: Journal Article
• Authors: Northcott, Melissa; Gearing, Linden J; Nim, Hieu T; Nataraja, Champa; Hertzog, Paul; Jones, Sarah A; Morand, Eric F
• Is Part Of: Lancet. Volume 3:Number 5(2021)
• Page Start: e357
• Page End: e370
• Publication Date: 2021-05
• Subjects: Rheumatology -- periodicals; 616.72305
• DOI: 10.1016/S2665-9913(21)00006-0
• Languages: English
• ISSNs: 2665-9913

Abstract

Summary: Background: Glucocorticoids, used as a therapy in systemic lupus erythematosus (SLE), interact with the cytoplasmic glucocorticoid receptor to modulate gene transcription. Minimising the use of glucocorticoids is a goal in SLE; however, pharmacological measures to support clinical guidelines are scarce. We evaluated glucocorticoid-regulated genes for their potential use as biomarkers of glucocorticoid exposure in SLE. We examined interactions between changes in gene expression that are induced by glucocorticoids and type I interferon. Methods: Genes regulated by glucocorticoids and type I interferon were analysed in relation to glucocorticoid exposure in adult patients meeting the American College of Rheumatology criteria for SLE from three cross-sectional cohorts: a local cohort from a tertiary hospital in Melbourne, VIC, Australia, and two public datasets (GSE49454, Hospital de la Conception, Marseille, France, and GSE88884, patients enrolled in a large, multicentre clinical trial). RNA sequencing was done using RNA from healthy donor leucocytes treated with the glucocorticoid dexamethasone, or type I interferon, or both. Findings: Glucocorticoid-regulated genes were analysed in a local SLE cohort (n=18) and public dataset GSE49454 (n=62). Five genes correlated with glucocorticoid dose in both cohorts and were combined to make a glucocorticoid gene signature. Validity of the glucocorticoid gene signature was tested in the public dataset GSE88884 (n=1756). A dose-dependent association was observed with glucocorticoid dose (p<0·0001), and the glucocorticoid gene signature had moderate ability to identify patients taking high-dose glucocorticoid (area under the curve [AUC]=0·77) although was less discriminatory when including all doses (AUC=0·69). We saw no effect of glucocorticoid dose on type I interferon -regulated gene expression. Patients with a high type I interferon gene signature had reduced glucocorticoid gene signature expression compared with patients with a low type I interferon gene signature matched for glucocorticoid dose, suggesting type I interferon inhibits glucocorticoid-stimulated gene expression. In RNA sequencing experiments, type I interferon impaired the expression of glucocorticoid-induced genes, whereas dexamethasone had minimal effect on the expression of type I interferon-stimulated genes. We identified genes regulated by dexamethasone but not affected by type I interferon; combined signatures using these genes also showed moderate ability to distinguish patients taking glucocorticoids. Interpretation: A gene signature for glucocorticoid exposure was identified, but the substantial effect of type I interferon on glucocorticoid-induced genes might limit its application in SLE. These data confirm the insensitivity of type I interferon-regulated genes to glucocorticoids, and together support the concept that type I interferon has a role in glucocorticoid resistance in SLE. Funding: Lupus Research Alliance and Australian National Health and Medical Research Council.