Abstract
Elevated cholesterol poses a significant cardiovascular risk, particularly in older women. The glucocorticoid receptor (GR), a crucial nuclear transcription factor that regulates the metabolism of virtually all major nutrients, harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene encoding the GR, rs6190, associated with increased cholesterol levels in women according to UK Biobank and All Of Us datasets. In SNP-genocopying transgenic mice, we found that the rs6190 SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors in liver respectively. Accordingly, in mice the rs6190 SNP was sufficient to elevate circulating cholesterol levels across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo knockdown of Pcsk9 and Bhlhe40 in liver. Remarkably, we found that this mechanism was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.