The human glucocorticoid receptor variant rs6190 increases blood cholesterol and promotes atherosclerosis.

Summary

A common GR coding variant (rs6190) elevates circulating cholesterol and atherosclerosis risk via hepatic transactivation of PCSK9 and BHLHE40, suppressing LDLR/HDLR. The effect shows sex specificity: attenuated by corticosterone/testosterone in males and additive with estrogen loss in females; mechanisms validate in CRISPR-edited human hepatocyte-like cells.

Key Findings

• rs6190 associates with higher cholesterol in women in UK Biobank and All of Us.
• SNP-genocopy mice show hepatic GR-driven transactivation of Pcsk9 and Bhlhe40, elevating all lipoprotein fractions and atherosclerosis.
• Liver knockdown of Pcsk9/Bhlhe40 abrogates atherogenesis; CRISPR-edited human hepatocyte-like cells recapitulate the mutant program.
• Corticosterone/testosterone mitigate, while estrogen loss augments, the mutant GR lipid program.

Clinical Implications

Highlights PCSK9/BHLHE40 as mediators of GR-driven hypercholesterolemia, supporting intensified lipid-lowering (e.g., PCSK9 inhibition) in genetically at‑risk women and prompting consideration of sex hormones’ modulatory roles.

Limitations

• Translational extrapolation from mouse hAPOE*2/*2 background to human pathophysiology may not fully capture complexity.
• Population associations, while robust, are observational and do not quantify clinical benefit of targeted interventions.

Future Directions

Assess clinical lipid/atherosclerosis outcomes by rs6190 genotype under PCSK9 inhibition and evaluate sex hormone interactions; explore BHLHE40 as a therapeutic target.