biostudies-literatureNguyen TTLMayo Graduate School of Biomedical SciencesMayo Research FoundationNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Alcohol Abuse and AlcoholismNIAAA NIH HHSNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS11635-11653https://www.ebi.ac.uk/biostudies/studies/S-EPMC9723631biostudies-literatureUnknown50(20)Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were 'unmasked' only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.Nucleic acids researchGlucocorticoids unmask silent non-coding genetic risk variants for common diseases.PMC9723631R01 AA027486R01 DK126827R01AA027486R01DK058185P30 CA015083U19 GM061388R01DK126827R01 DK058185U19GM61388R01 GM028157R01GM28157Li HOrdog TZhang HGao HZhang LYu JPhilips TJNguyen TTLCopenhaver KYe ZGaspar-Maia AWang LShi GXLiu DBarath ALuong MZhang CWeinshilboum RMWei LLee JHfalseGlucocorticoids unmask silent non-coding genetic risk variants for common diseases.Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were 'unmasked' only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.2022-01-01T00:00:00Z2022 Nov2026-04-08T15:38:30.481Z2025-04-04T23:36:54.134ZS-EPMC97236313639950810.1093/nar/gkac1045