Glucocorticoids unmask silent non-coding genetic risk variants for common diseases

Thanh Thanh L. Nguyen, Huanyao Gao, Duan Liu, Trudy Janice Philips, Zhenqing Ye, Jeong Heon Lee, Geng Xian Shi, Kaleigh Copenhaver, Lingxin Zhang, Lixuan Wei, Jia Yu, Huan Zhang, Abhijeet Barath, Maggie Luong, Cheng Zhang, Alexandre Gaspar-Maia, Hu Li, Liewei Wang, Tamas Ordog, Richard M. Weinshilboum

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)11635-11653
Number of pages19
JournalNucleic acids research
Issue number20
StatePublished - Nov 11 2022

ASJC Scopus subject areas

  • Genetics


Dive into the research topics of 'Glucocorticoids unmask silent non-coding genetic risk variants for common diseases'. Together they form a unique fingerprint.

Cite this