OR29-07 The Rs6190 Polymorphism Unveils Unprecedented Mechanisms Of Cardiovascular Health Elicited By The Glucocorticoid Receptor In Humans And Mice

Abstract Disclosure: M. Quattrocelli: None. Genetic variations in the glucocorticoid receptor (GR) gene NR3C1, such as the single nucleotide polymorphism (SNP) rs6190 (p.R23K), have been associated to changes in metabolism and cardiovascular health, but mechanisms of action and relevance in large human cohorts remain unaddressed. We probed the large UK Biobank and All of Us datasets for the rs6190 polymorphism (up to 3% minor allele frequency according to genetic ancestry) and found it significantly associated in a zygosity-dependent manner to changes in glycemia, A1C, lean mass and BMI. To elucidate the mechanisms underlying these effects, we generated transgenic knock-in mice genocopying this polymorphism. Compared to non-mutant littermates, mutant mice exhibited increased muscle insulin sensitivity and strength, mitigating diet-induced adverse effects on weight gain and exercise intolerance. RNA-seq and ChIP-seq profiling in skeletal muscle revealed that the mutant GR enhanced transactivation of Foxc1 and Arid5A, genes with unknown function in muscle. We found that Foxc1 was required and sufficient to activate expression of insulin response pathway genes Insr and Irs1, while Arid5a was required and sufficient to repress transcription of the lipid uptake genes Cd36 and Fabp4, reducing muscle di- and triacylglycerol accumulation. Additionally, the rs6190 SNP associated with a zygosity-dependent elevation of cholesterol levels in women in both UK Biobank and All Of Us datasets. In SNP-genocopying transgenic mice, the SNP enhanced hepatic GR activity, transactivating Pcsk9 and Bhlhe40, which are negative regulators of LDL and HDL receptors, respectively. This led to increased circulating cholesterol levels and heightened atherosclerotic risk, particularly on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was mitigated by in vivo knockdown of Pcsk9 and Bhlhe40 in the liver. This mechanism was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Our findings leverage a non-rare human variant to uncover novel GR mechanisms and transactivation targets determining cardiovascular health in humans and mice. Presentation: Monday, July 14, 2025