Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple patient-derived adipose stem cell-derived adipocytes and iPSC-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Patient-specific GR binding could be traced to single nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations and, remarkably, predicted metabolic side-effects of GC-treated patients. These data validate a patient stem cell-based experimental framework to discover genetic variants that impact GR function and individual responses to GC drugs, with implications for developing personalized therapies.